Alkynyl-containing tryptophan derivative inhibitors of tace/matrix metalloproteinase

ABSTRACT

This invention provides compounds of Formula I, having the structure:  
                 
that are useful in treating diseases or disorders mediated by TNF-α. The invention further provides methods for use of the compounds for treating such a disease or disorder or for alleviating symptoms thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser. No. 60/639,452 filed on Dec. 28, 2004, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to acetylenic aryl carboxylic acid inhibitors of TNF-α converting enzyme (TACE)/matrix metalloproteinase (MMP). The compounds of the present invention are useful in disease conditions mediated by TNF-α, such as rheumatoid arthritis (RA), juvenile RA, psoriatic arthritis, ankylosing spondylitis, psoriasis, osteoarthritis, tumor metastasis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, diabetes (insulin resistance), Crohn's disease, degenerative cartilage loss, asthma, idiopathic pulmonary fibrosis, vasculitis, systemic lupus erythematosus, irritable bowel syndrome, acute coronary syndrome, hepatitis C, cachexia, COPD (chronic obstructive pulmonary disease), and type 2 diabetes.

BACKGROUND OF THE INVENTION

TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5): 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6): 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29: 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5): 3] septic shock [Mathison et al. J. Clin. Invest. 1988, 81: 1925; Miethke et al. J. Exp. Med. 1992, 175: 91], graft rejection [Piguet, P. F. et al. J. Exp. Med. 1987, 166: 1280], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57: 505], anorexia, inflammation [Ksontini, R. et al. Arch. Surg. 1998, 133: 558], congestive heart failure [Packer, M. Circulation, 1995, 92(6): 1379; Ferrari, R. et al. Circulation, 1995, 92(6): 1479], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S. et al. Science, 1993, 259: 87] and HIV infection [Peterson, P. K. et al. J. Clin. Invest. 1992, 89: 574; Pallares-Trujillo, J. et al. Med. Res. Reviews, 1995, 15(6): 533], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230: 630]. For example, research with anti-TNF-α antibodies and transgenic animals has demonstrated that blocking the formation of TNF-α inhibits the progression of arthritis [Rankin, E. C. et al. Br. J. Rheumatol. 1995, 34: 334; Pharmaprojects, 1996, Therapeutic Updates 17(Oct.), au197-M2Z]. This observation has recently been extended to humans as well [“TNF-α in Human Diseases”, Current Pharmaceutical Design, 1996, 2: 662].

Because of the link between TNF-α and various disease states, it is expected that small molecule inhibitors of TACE/MMP would have the potential for treating such diseases. However, although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like, which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349: 20]. Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above. The present invention is directed to these, as well as other, important ends

SUMMARY OF THE INVENTION

In some embodiments, the present invention provides compounds having the Formula I:

wherein:

R₁ is H, aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, or C₄₋₈-cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR₅, S and O;

wherein each of said aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl or aralkyl can be optionally substituted with up to four independently selected R₁₄ groups;

R₂, R₃ and R₄ are each independently, H, C₁₋₈ alkyl, halogen, CN, CCH, OH, or OR₁;

R₅, R₆, R₇, R₈, R₉ and R₁₀ are each independently, H, aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aralkyl, heteroalkyl, heteroarylalkyl, halogen, CN, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, NR₁₁R₁₁, COOR₁₁, OR₁₁, or C₄₋₈ cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR₁₁, S and O;

wherein each of said aryl, heteroaryl, heteroalkyl, heteroarylalkyl, C₄₋₈ cycloheteroalkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, or aralkyl can be optionally substituted with up to four independently selected R₁₅ groups;

wherein one or more than one of the pairs R₄ and R₆, R₄ and R₇, R₅ and R₆, R₅ and R₁₀, R₇ and R₈, R₈ and R₉ or R₉ and R₁₀, together with the carbon atom or atoms to which they are attached, can form a cycloalkyl ring having 3-8 carbon atoms, or a C₄₋₈ cycloheteroalkyl ring;

R₁₁ is H, aryl, heteroaryl, aralkyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, oxy, halogen, hydroxyalkyl, alkoxy, alkoxy-alkyl, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, C₁₋₈ alkanoyl, COOR₁, COR₁, SO₂—C₁₋₈ alkyl, SO₂-aryl, SO₂-heteroaryl, or CO—NHR₁;

wherein each of said aryl, heteroaryl, aralkyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, SO₂—C₁₋₈ alkyl, SO₂-aryl and SO₂-heteroaryl can be optionally substituted with up to four independently selected R₁₆ groups;

each R₁₄, R₁₅ and R₁₆ is, independently, halogen, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, —OR₁₇, CN, COR₁₂, C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ perhaloalkoxy, C₁₋₆ perfluoroalkyl, —O—C₁₋₆ perfluoroalkyl, CONR₁₂R₁₃, —OPO(OR_(12a))OR_(13a), —PO(OR_(12a))R₁₃, —OC(O)OR_(12a), —O—C₁₋₆ alkyl-NR₁₂R₁₃, —OC(O)NR₁₂R₁₃, —C(O)NR₁₂OR_(13a), —COOR_(12a), —SO₃H, —NR₁₂R₁₃, —N(R₂₀)(C₁₋₆ alkyl)NR₁₂, —N(R₂₀)COR₁₃, —N(R₂₀)COOR_(13a), —SO₂NR₁₂R₁₃, NO₂, —N(R₂₀)SO₂R₁₃, —N(R₂₀)CONR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)NR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)N(SO₂R₁₂)R₁₃, —N(R₂₀)C(═NR₁₃)N(C═OR₁₂)R₁₃, -tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR₁₂R₁₃, aryl, phenyl, heteroaryl, —C₅₋₈ cycloheteroalkyl, CH₂—OR₂₂, —SR₂₂, —CH₂—SR₂₂, —SO₂NR₁₂R₁₃, —C(═NR₂₂)—, —C(NCN)R₂₂—, —CSN(R₂₂)₂, —C(NH)N(R₂₂)₂, NO₂, NO₃, azido, hydrazino, hydroxylamino, disulfide, urea, guanidine or —S(O)_(r)R₁₂ wherein n is 0, 1 or 2;

or any two R₁₄, R₁₅ or R₁₆ groups when attached to an aryl, aralkyl, heteroaryl or heteroarylalkyl group can together form a group of formula —O—(CH₂)_(k)—O— wherein k is 1 or 2;

each R₁₂ and R₁₃ is, independently, H, OH, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl; or —NR₁₂R₁₃ may form a pyrrolidine, piperidine, morpholine, thiomorphohne, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring;

each R_(12a) and R_(13a) is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₃ perfluoroalkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl;

each R₂₀ is, independently, H or C₁₋₆ alkyl;

each R₁₇ is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl or C₄₋₈ cycloheteroalkyl;

R₂₁ is H or C₁₋₈ alkyl;

each R₂₂ is, independently, H or C₁₋₃ alkyl;

A is SO₂ or —P(O)—R₁₀;

X is O, NH, CH₂ or S; and

Y is aryl or heteroaryl;

with the proviso that A and X are not bonded to adjacent atoms of Y;

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, compounds are provided having the Formula II:

wherein the constituent variables are as described above, or a pharmaceutically acceptable salt or prodrug thereof.

The compounds of the present invention are useful for the treatment of disease conditions mediated by TNF-α, such as rheumatoid arthritis (RA), juvenile RA, psoriatic arthritis, ankylosing spondylitis, psoriasis, osteoarthritis, tumor metastasis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, diabetes (insulin resistance), Crohn's disease, degenerative cartilage loss, asthma, idiopathic pulmonary fibrosis, vasculitis, systemic lupus erythematosus, irritable bowel syndrome, acute coronary syndrome, hepatitis C, cachexia, COPD, and type 2 diabetes and for the alleviation of symptoms thereof.

The present invention further provides methods of using the compounds described herein. In some embodiments, the methods include identifying a mammal having a disease or disorder mediated by TNF-α, and providing to the mammal an effective amount of a compound as described herein.

In further embodiments, the methods include identifying a mammal having a symptom of a disease or disorder mediated by TNF-α, and providing to the mammal an amount of a compound as described herein effective to ameliorate the symptom.

DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to compounds that are inhibitors of TNF-α converting enzyme (TACE) and matrix metalloproteinases (MMPs). In some embodiments, the compounds have the Formula I:

wherein:

R₁ is H, aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, or C₄₋₈-cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR₅, S and O; wherein each of said aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl or aralkyl can be optionally substituted with up to four independently selected R₁₄ groups;

R₂, R₃ and R₄ are each, independently, H, C₁₋₈ alkyl, halogen, CN, CCH, OH, or OR₁;

R₅, R₆, R₇, R₈, R₉ and R₁₀ are each, independently, H, aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ cycloalkyl, aralkyl, heteroalkyl, heteroarylalkyl, halogen, CN, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, NR₁₁R₁₁, COOR₁₁, OR₁₁, or C₄₋₈ cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR₁₁, S and O;

wherein each of said aryl, heteroaryl, heteroalkyl, heteroarylalkyl, C₄₋₈ cycloheteroalkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, or aralkyl can be optionally substituted with up to four independently selected R₁₅ groups;

wherein one or more than one of the pairs R₄ and R₆, R₄ and R₇, R₅ and R₆, R₅ and R₁₀, R₇ and R₈, R₈ and R₉ or R₉ and R₁₀, together with the carbon atom or atoms to which they attached, can form a cycloalkyl ring having 3-8 carbon atoms, or a C₄₋₈ cycloheteroalkyl ring;

R₁ is H, aryl, heteroaryl, aralkyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, oxy, halogen, hydroxyalkyl, alkoxy, alkoxy-alkyl, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, C₁₋₈ alkanoyl, COOR₁, COR₁, SO₂—C₁₋₈ alkyl, SO₂-aryl, SO₂-heteroaryl, or CO—NHR₁;

wherein each of said aryl, heteroaryl, aralkyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, SO₂—C₁₋₈ alkyl, SO₂-aryl and SO₂-heteroaryl can be optionally substituted with up to four independently selected R₁₆ groups;

each R₁₄, R₁₅ and R₁₆ is, independently, halogen, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, —OR₁₇, CN, COR₁₂, C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ perhaloalkoxy, C₁₋₆ perfluoroalkyl, —O—C₁₋₆ perfluoroalkyl, CONR₁₂R₁₃, —OPO(OR_(12a))OR_(13a), —PO(OR_(12a))R₁₃, —OC(O)OR_(12a), —O—C₁₋₆ alkyl-NR₁₂R₁₃, —OC(O)NR₁₂R₁₃, —C(O)NR₁₂OR_(13a), —COOR_(12a), —SO₃H, —NR₁₂R₁₃, —N(R₂₀)(C₁₋₆ alkyl)NR₁₂, —N(R₂₀)COR₁₃, —N(R₂₀)COOR_(13a), —SO₂NR₁₂R₁₃, NO₂, —N(R₂₀)SO₂R₁₃, —N(R₂₀)CONR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)NR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)N(SO₂R₁₂)R₁₃, —N(R₂₀)C(═NR₁₃)N(C═OR₁₂)R₁₃, -tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR₁₂R₁₃, aryl, phenyl, heteroaryl, —C₅₋₈ cycloheteroalkyl, CH₂—OR₂₂, —SR₂₂, —CH₂—SR₂₂, —SO₂NR₁₂R₁₃, —C(═NR₂₂)—, —C(NCN)R₂₂—, —CSN(R₂₂)₂, —C(NH)N(R₂₂)₂, NO₂, NO₃, azido, hydrazino, hydroxylamino, disulfide, urea, guanidine, or —S(O)_(n)R₁₂ wherein n is 0, 1 or 2;

or any two R₁₄, R₁₅ or R₁₆ groups when attached to an aryl, aralkyl, heteroaryl or heteroarylalkyl group can together form a group of formula —O—(CH₂)_(k)—O— wherein k is 1 or 2;

each R₁₂ and R₁₃ is, independently, H, OH, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl; or —NR₁₂R₁₃ may form a pyrrolidine, piperidine, morpholine, thiomorphohne, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring;

each R_(12a) and R_(13a) is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₃ perfluoroalkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl;

each R₂₀ is, independently, H or C₁₋₆ alkyl;

each R₁₇ is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl or C₄₋₈ cycloheteroalkyl;

R₂₁ is H or C₁₋₈ alkyl;

each R₂₂ is, independently, H or C₁₋₃ alkyl;

A is SO₂ or —P(O)—R₁₀;

X is O, NH, CH₂ or S; and

Y is aryl or heteroaryl;

with the proviso that A and X are not bonded to adjacent atoms of Y;

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, A is SO₂. In some further embodiments, X is O. In some further embodiments, Y is aryl, preferably phenyl.

In some further embodiments, Y is heteroaryl, preferably pyridyl, thienyl, furanyl, imidazolyl, triazolyl or thiadiazolyl.

In some embodiments, R₁ is H or C₁₋₆ alkyl. In some further embodiments, R₂ and R₃ are each H. In still further embodiments, R₇ is H. In some embodiments, R₂, R₃ and R₇ are each H.

In some embodiments, R₁ is H or C₁₋₆ alkyl; R₂, R₃ and R₇ are each H; A is SO₂; X is O; and Y aryl, preferably phenyl.

In some preferred embodiments, the compounds of the invention have the Formula II:

wherein the constituent variables are as described above.

In some embodiments of the compounds having Formula II, R₅ is H, C₁₋₆ alkyl, C₂₋₈ alkenyl, arylalkyl, cycloalkylalkyl, CO₂R₁₁, aryloxyalkyl or heteroarylalkyl, wherein said arylalkyl is optionally substituted with up to four substituents independently selected from the group consisting of C₁₋₆ alkyl, halogen, C₁₋₈ alkoxy, aryl, phenyl, C₁₋₃ haloalkyl, C₁₋₃ perhaloalkyl, C₁₋₃ haloalkoxy, C₁₋₃ perhaloalkoxy, CN, alkenyloxy, CO₂H and OH, wherein any two adjacent hydroxyl groups attached to the aryl moiety of said arylalkyl can be joined together to form a 1,3-dioxolane group; R₆ is H or C₁₋₆ alkyl; R₈ is H, C₁₋₆ alkyl, C₁₋₄ alkoxy, OH, arylalkoxy, halogen, CO₂H or CN; R₉ is H, halogen or C₁₋₆ alkyl; R₁₀ is H or C₁₋₆ alkyl; and R₁₁ is C₁₋₆ alkyl.

In some embodiments of the compounds of Formula II, R₄ is H. In further embodiments of the compounds of Formula II, R₅ is H or arylalkyl, wherein said arylalkyl is optionally substituted with up to three C₁₋₃ alkoxy groups. In further embodiments of the compounds of Formula II, R₆ is H or methyl. In further embodiments of the compounds of Formula II, R₈ is H, halogen, C₁₋₃ alkyl, or C₁₋₃ alkoxy. In still further embodiments of the compounds of Formula II, R₉ is H, or R₁₀ is H, or R₉ and R₁₀ are each H. In further embodiments of the compounds of Formula II, R₄, R₉ and R₁₀ are each H.

In further embodiments of the compounds of Formula II, R₄, R₉ and R₁₀ are each H; R₅ is H or arylalkyl, wherein said arylalkyl is preferably benzyl, which is optionally substituted with up to three C₁₋₃ alkoxy groups, preferably methoxy groups; R₆ is H or methyl; and R₈ is H, halogen, C₁₋₃ alkyl, preferably methyl, or C₁₋₃ alkoxy, preferably methoxy.

Also provided in accordance with the present invention are pharmaceutically acceptable salts, and prodrugs, of the compounds disclosed herein.

The compounds of the present invention are useful for the treatment of disease conditions mediated by TNF-α, such as rheumatoid arthritis (RA), juvenile RA, psoriatic arthritis, ankylosing spondylitis, psoriasis, osteoarthritis, tumor metastasis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, diabetes (insulin resistance), Crohn's disease, degenerative cartilage loss, asthma, idiopathic pulmonary fibrosis, vasculitis, systemic lupus erythematosus, irritable bowel syndrome, acute coronary syndrome, hepatitis C, cachexia, COPD, and type 2 diabetes and for the alleviation of symptoms thereof. Accordingly, the present invention further provides methods of treating these diseases and disorders using the compounds described herein. In some embodiments, the methods include identifying a mammal having a disease or disorder mediated by TNF-α, and providing to the mammal an effective amount of a compound as described herein.

In further embodiments, the methods are provided for alleviating a symptom of a disease or disorder mediated by TNF-α. In some embodiments, the methods include identifying a mammal having a symptom of a disease or disorder mediated by TNF-α, and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., lessen the severity of) the symptom.

Pharmaceutically acceptable salts of the compounds of Formula (I) having an acidic moiety can be formed from organic and inorganic bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Internal salts may furthermore be formed. Similarly, when a compound of the present invention contains a basic moiety, salts can be formed from organic and inorganic acids. For example salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known pharmaceutically acceptable acids.

The present invention also includes prodrugs of the compounds described herein. As used herein, “prodrug” refers to a moiety that releases a compound of the invention when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Examples of prodrugs include compounds of the invention as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a mammalian subject, cleaves in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entireties.

As used herein, the term “alkyl” is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. Alkyl groups can contain from 1 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. In some embodiments, alkyl groups can be substituted with up to four substituent groups, as described below. As used herein, the term “lower alkyl” is intended to mean alkyl groups having up to six carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like. In some embodiments, alkenyl groups can be substituted with up to four substituent groups, as described below.

As used herein, “alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. In some embodiments, alkynyl groups can be substituted with up to four substituent groups, as described below.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclic groups including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or poly-cyclic ring (e.g., 2, 3, or 4 fused ring) systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (indanyl), cyclohexane (tetrahydronaphthyl), and the like.

As used herein “cycloalkylalkyl” refers to a group of formula -alkyl-cycloalkyl, for example a cyclopropylmethyl group.

As used herein, “hydroxy” or “hydroxyl” refers to OH.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

As used herein, “cyano” refers to CN.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. An alkoxy group can contain from 1 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. In some embodiments, alkoxy groups can be substituted with up to four substituent groups, as described below.

As used herein, “alkenyloxy” refers to an —O-alkenyl group. Examples of alkenyloxy groups include prop-3-enyloxy, but-2-enyloxy, but-3-enyloxy, pent-2-enyloxy, 2-methyl-pent-3-enyloxy and the like. Alkenyloxy groups can contain from 2 to about 20, 2 to about 10, 2 to about 8, 2 to about 6, 2 to about 4, or 2 to about 3 carbon atoms.

As used herein, “alkynyloxy” refers to an —O-alkynyl group. Examples of alkenyloxy groups include prop-3-ynyloxy, but-2-ynyloxy, but-3-ynyloxy, pent-2-ynyloxy, 2-methyl-pent-3-ynyloxy and the like. Alkynyloxy groups can contain from 2 to about 20, 2 to about 10, 2 to about 8, 2 to about 6, 2 to about 4, or 2 to about 3 carbon atoms.

As used herein, the term “perfluoroalkoxy” indicates a group of formula —O— perfluoroalkyl.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in which all of the hydrogen atoms are replaced with halogen atoms can be referred to as “perhaloalkyl.” Examples perhaloalkyl groups include CF₃ and C₂F₅.

As used herein, “haloalkoxy” refers to an -O-haloalkyl group.

As used herein, “aryl” refers to aromatic carbocyclic groups including monocyclic or polycyclic aromatic hydrocarbons such as, for example, phenyl, 1-naphthyl, 2-naphthyl anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some preferred embodiments, aryl groups are phenyl or naphthyl groups that optionally contain up to four, preferably up to 2, substituent groups as described below.

As used herein, “heteroaryl” is intended to refer to aromatic heterocyclic groups that have at least one heteroatom ring member selected from N, S and O. In some embodiments, one or more ring nitrogen atoms can bear a substituent as described herein. In some embodiments, heteroaryl groups can be monocyclic systems or polycyclic aromatic ring systems having from 5 to 10 ring atoms. Examples of heteroaryl groups include, without limitation, the following:

wherein K is defined as O, S, N or NR₁₁, where R₁₁ is as defined supra. Examples of some preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. In some preferred embodiments, heteroaryl groups can be substituted with up to four, preferably up to 2, substituent groups as described below.

As used herein, “aryloxy” refers to an —O-aryl group, for example and not with limitation, phenoxy.

As used herein, “arylalkyl” or “aralkyl” refers to a group of formula -alkyl-aryl. Preferably, the alkyl portion of the arylalkyl group is a lower alkyl group, i.e., a C₁ alkyl group, more preferably a C₁₋₃ alkyl group. Examples of aralkyl groups include benzyl and naphthylmethyl groups. In some preferred embodiments, arylalkyl groups can be optionally substituted with up to four, preferably up to 2, substituent groups as described below.

As used herein, “heteroarylalkyl” or “heteroaralkyl” refers to a group of formula -alkyl-heteroaryl. Nonlimiting examples of heteroaralkyl groups include pyridylmethyl and pyrrolemethyl groups. In some preferred embodiments, heteroarylalkyl groups can be substituted with up to four, preferably up to 2, substituent groups as described below.

At various places in the present specification substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C₁₋₆ alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, etc.

In some embodiments, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkenyloxy, alkynyloxy, haloalkyl, haloalkoxy, aryl, heteroaryl, aryloxy, arylalkyl and heteroarylalkyl groups of the compounds of the invention can be substituted with one or more, preferably up to four, and more preferably one or two substituent groups. Examples of suitable substituent groups include halogen, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, —OR₁₇, CN, COR₁₂, C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ perhaloalkoxy, C₁₋₆ perfluoroalkyl, —O—C₁₋₆ perfluoroalkyl, CONR₁₂R₁₃, —OPO(OR_(12a))OR_(13a), —PO(OR_(12a))R₁₃, —OC(O)OR_(12a), —O—C₁₋₆ alkyl-NR₁₂R₁₃, —OC(O)NR₁₂R₁₃, —C(O)NR₁₂OR_(13a), —COOR_(12a), —SO₃H, —NR₁₂R₁₃, —N(R₂₀)(C₁₋₆ alkyl)NR₁₂, —N(R₂₀)COR₁₃, —N(R₂₀)COOR_(13a), —SO₂NR₁₂R₁₃, NO₂, —N(R₂₀)SO₂R₁₃, —N(R₂₀)CONR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)NR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)N(SO₂R₁₂)R₁₃, —N(R₂₀)C(═NR₁₃)N(C═OR₁₂)R₁₃, -tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR₁₂R₁₃, aryl, phenyl, heteroaryl, —C₅₋₈ cycloheteroalkyl, CH₂—OR₂₂, —SR₂₂, —CH₂—SR₂₂, —SO₂NR₁₂R₁₃, —C(═NR₂₂)—, —C(NCN)R₂₂—, —CSN(R₂₂)₂, —C(NH)N(R₂₂)₂, NO₂, NO₃, azido, hydrazino, hydroxylamino, disulfide, urea, guanidine or —S(O)_(n)R₁₂ wherein n is 0, 1 or 2;

wherein:

each R₁₂ and R₁₃ is, independently, H, OH, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl; or —NR₁₂R₁₃ can form a pyrrolidine, piperidine, morpholine, thiomorphohne, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring;

each R_(12a) and R_(13a) is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₃ perfluoroalkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl;

each R₂₀ is, independently, H or C₁₋₆ alkyl; and

each R₂₂ is, independently, H or C₁₋₃ alkyl.

Examples of some preferred substituents include halogen, CH₃, C₂H₅, vinyl, allyl, —C≡CH, —OH, OCH₃, OCH₂CH₃, SH, SCH₃, SCH₂CH₃, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, CN, COH, CONH₂, SOCH₃, SO₂CH₃, SO₃H, CO₂H, CO₂CH₃, —OCO₂H, —OCO₂CH₃, —OCH₂NH₂, —C(O)NH₂, —C(O)N(CH₃)₂, —OC(O)NH₂, —OC(O)N(CH₃)₂, —NH₂, —N(CH₃)₂, —NHCOCH₃, —SO₂NH₂, SO₂N(CH₃)₂, NO₂, —NHSO₂CH₃, —NHCONH₂, —NHCON(CH₃)₂, CH₂OH, —SH, —SCH₃, —CH₂—SH, CH₂—SCH₃, —SO₂NH₂, —C(═NH)—, NO₂, NO₃, azido, hydrazino, hydroxylamino, disulfide, urea or guanidine.

As used in accordance with this invention, the term “providing,” with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a prodrug, derivative, or analog which will form the effective amount of the compound or substance within the body. This invention also covers providing the compounds of this invention to treat the disease states disclosed herein that the compounds are useful for treating.

The compounds of the present invention can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

The novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.

The compounds of present invention can be conveniently prepared in accordance with the procedures outlined in the schemes below, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the invention.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.

Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

Although not wishing to be limited to any source, publications and literatures such as PCT Application No, WO 200044723; Li, J. P., et al. Synthesis, 1988, 73-76; Gilchrist, T. L. and T. G. Roberts, J. Chem. Soc. Perkin. Trans 1 1983, 1283-1292 are useful and recognized references of organic synthesis known to those in the art. Each of the foregoing is incorporated herein by reference in its entirety.

General Schemes for the Preparation of the Present Invention Compounds

Compounds of the invention can be prepared according to the convenient synthetic route in Scheme 1.

As shown in Scheme 1, a mono or poly substituted tryptophan derivative 1 is reacted with 4-but-2-ynyloxy-benzenesulfonyl chloride 2 (prepared by using the procedures described in WO 200044723, incorporated by reference herein in its entirety) in the presence of base such as triethylamine at room temperature to afford arylsulfonamido tryptophan derivative 3. Tryptophan derivatives 1 are commercially available, or can be synthesized using standard methods known to those skilled in the art.

Compounds of the present invention also can be prepared according to the synthetic route shown in Scheme 2.

As shown in Scheme 2, an N-Boc-protected tryptophan derivative 4 is reacted with a halide such as R₅Br or R₅I in the presence of base such as NaH at low temperature (0° C.) to afford a substituted N-Boc-protected tryptophan derivative 5. Tryptophan derivatives 4 are commercially available, or can be synthesized using standard methods known to those skilled in the art. The Boc protecting group is then removed under acidic conditions, for example, using trifluoroacetic acid (TFA) in a solvent such as dichloromethane, to afford a substituted tryptophan 6. Coupling of 6 with 4-but-2-ynyloxy-benzenesulfonyl chloride 2 in the presence of a base such as triethylamine at room temperature produces the arylsulfonamido tryptophan derivative 7. The overall yields from the three steps shown in Scheme 2 are generally moderate (i.e., 50%-60%) to high (i.e., 80%-90%).

Compounds of the present invention also can be prepared according to the synthetic route in Scheme 3, below.

As shown in Scheme 3, an indole derivative 8 is reacted with oxime 9 in the presence of base, such as Na₂CO₃, in solvent, such as methylene chloride, at room temperature to afford an indole-oxime complex 10 as regioisomers. Oxime 9 is prepared by using literature procedures described in (a) Li, J. P. et al. Synthesis, 1988, 73-76 or (b) Gilchrist, T. L. and T. G. Roberts, J. Chem. Soc. Perkin. Trans 1 1983, 1283-1292, each of which is incorporated herein by reference in its entirety. The reduction of complex 10 to tryptophan ester ammonium salt 11 is achieved by 1) treating complex 10 with zinc powder in acetic acid to reduce the oxime to an amino group; followed by 2) conversion of the amino group into the ammonium salt with hydrochloric acid. Coupling of 11 with 4-but-2-ynyloxy-benzenesulfonyl chloride 2 in the presence of base such as triethylamine at room temperature produces arylsulfonamido tryptophan ester derivative 12. The arylsulfonamido tryptophan ester derivative 12 is reacted with a desired halide such as R₅Br or R₅₁ in the presence of base such as NaH at low temperature (0° C.) to afford another substituted arylsulfonamido tryptophan ester derivative 13. Hydrolysis of the ester group of 13 with base, such as a 2N aqueous NaOH solution, in solvent, such as a methanol/tetrahydrofuran mixture, at room temperature affords arylsulfonamido tryptophan derivative 14. The overall yield of the five steps from 8 to 14 is generally about 20% to about 50%.

EXAMPLES Examples 1-224

Preparation of Compounds of the Invention

The following describes the preparation of representative compounds of this invention in greater detail. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially the same results.

Mass spectral data is reported as the mass-to-charge ratio, m/z, and for high resolution mass spectral data, the calculated and experimentally found masses, [M+H]⁺, for the neutral formulae M are reported. Nuclear magnetic resonance data is reported as δ in parts per million (ppm) downfield from the standard, tetramethylsilane, along with the solvent, nucleus, and field strength parameters. The spin-spin homonuclear coupling constants are reported as J values in hertz, and the multiplicities are reported as a: s, singlet; d, doublet; t, triplet; q, quartet; quintet; or br, broadened.

General Methods

1. Semi-preparative RP-HPLC conditions:

-   -   Gilson Semi-Preparative Reverse Phase HPLC system with Unipoint         Software     -   Column: 50×19 mm Xterra C18, 5 micron column at 50° C.     -   Solvent A: Water (0.02% TFA buffer); Solvent B: Acetonitrile         (0.02% TFA buffer)     -   Solvent Gradient (16 min method): Time 0: 10% B; 2.5 min: 10% B;         12 min: 95% B; 14 min: 95% B; 14.1 min: 10% B; 16 min: 10% B     -   Flow rate: 22.5 mL/min     -   Detection: 254 nm DAD         2. Analytical LCMS conditions:     -   Hewlett Packard 1100 MSD with ChemStation Software     -   Column: 30×2.1 mm Xterra C18 MS, 5 micron particle size at 50°         C.     -   Solvent A: Water (0.02% formic acid buffer)     -   Solvent B: Acetonitrile (0.02% formic acid buffer)     -   Gradient: Time 0: 5% B; 3.5 min: 95% B; 5 min: 95% B     -   Flow rate 1.0 mL/min     -   Injection volume: 5 μL     -   Sample concentration: ˜2.0 mM     -   Detection: 220 nm, 254 nm DAD; API-ES Scanning Mode Positive         150-700; Fragmentor 70 mV

The following compounds were prepared using the procedures of Schemes 1-3 described above: LCMS Retention Calculated Time Observed Example Compound Name MW (min) MW 1 N-{[4-(but-2- 412 2.45 413 [M + H] ynyloxy)phenyl]sulfonyl}-D- tryptophan 2 N-{[4-(but-2- 412 2.39 413 [M + H] ynyloxy)phenyl]sulfonyl}-L- tryptophan 3 N-{[4-(but-2- 430 2.60 431 [M + H] ynyloxy)phenyl]sulfonyl}-5- fluorotryptophan 4 N-{[4-(but-2- 442 2.50 443 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxytryptophan 5 N-{[4-(but-2- 428 2.14 429 [M + H] ynyloxy)phenyl]sulfonyl}-5- hydroxytryptophan 6 N-{[4-(but-2- 426 2.69 427 [M + H] ynyloxy)phenyl]sulfonyl}-5- methyltryptophan 7 N-{[4-(but-2- 430 2.61 431 [M + H] ynyloxy)phenyl]sulfonyl}-6- fluorotryptophan 8 N-{[4-(but-2- 426 2.70 427 [M + H] ynyloxy)phenyl]sulfonyl}-6- methyltryptophan 9 N-{[4-(but-2- 426 2.72 427 [M + H] ynyloxy)phenyl]sulfonyl}-alpha- methyltryptophan 10 N-{[4-(but-2- 426 2.67 427 [M + H] ynyloxy)phenyl]sulfonyl}-7- methyltryptophan 11 N-{[4-(but-2- 428 2.13 429 [M + H] ynyloxy)phenyl]sulfonyl}-5-hydroxy- L-tryptophan 12 N-{[4-(but-2- 455 3.03 456 [M + H] ynyloxy)phenyl]sulfonyl}-1-propyl-L- tryptophan 13 1-butyl-N-{[4-(but-2- 469 3.19 470 [M + H] ynyloxy)phenyl]sulfonyl}-L- tryptophan 14 N-{[4-(but-2- 469 3.17 470 [M + H] ynyloxy)phenyl]sulfonyl}-1-isobutyl- L-tryptophan 15 1-allyl-N-{[4-(but-2- 453 2.95 454 [M + H] ynyloxy)phenyl]sulfonyl}-L- tryptophan 16 N-{[4-(but-2- 517 3.26 518 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- methylbenzyl)-L-tryptophan 17 N-{[4-(but-2- 517 3.27 518 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- methylbenzyl)-L-tryptophan 18 N-{[4-(but-2- 537 3.30 538 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- chlorobenzyl)-L-tryptophan 19 N-{[4-(but-2- 533 2.97 534 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- methoxybenzyl)-L-tryptophan 20 5-(benzyloxy)-N-{[4-(but-2- 518 2.99 519 [M + H] ynyloxy)phenyl]sulfonyl}tryptophan 21 N-{[4-(but-2- 426 2.76 427 [M + H] ynyloxy)phenyl]sulfonyl}-1-methyl- D-tryptophan 22 N-{[4-(but-2- 483 3.19 484 [M + H] ynyloxy)phenyl]sulfonyl}-1-pentyl-D- tryptophan 23 N-{[4-(but-2- 509 3.31 510 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclohexylmethyl)-D-tryptophan 24 N-{[4-(but-2- 561 3.27 562 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- phenoxybutyl)-D-tryptophan 25 1-benzyl-N-{[4-(but-2- 503 3.00 504 [M + H] ynyloxy)phenyl]sulfonyl}-D- tryptophan 26 N-{[4-(but-2- 517 3.13 518 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- methylbenzyl)-D-tryptophan 27 1-(1,1′-biphenyl-2-ylmethyl)-N-{[4- 579 3.34 580 [M + H] (but-2-ynyloxy)phenyl]sulfonyl}-D- tryptophan 28 N-{[4-(but-2- 521 3.02 522 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- fluorobenzyl)-D-tryptophan 29 N-{[4-(but-2- 553 3.32 554 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- naphthylmethyl)-D-tryptophan 30 N-{[4-(but-2- 504 2.29 505 [M + H] ynyloxy)phenyl]sulfonyl}-1-(pyridin- 3-ylmethyl)-D-tryptophan 31 N-{[4-(but-2- 467 3.02 468 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclopropylmethyl)-D-tryptophan 32 N-{[4-(but-2- 480 3.22 481 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclobutylmethyl)-D-tryptophan 33 N-{[4-(but-2- 523 3.44 522 [M − H] ynyloxy)phenyl]sulfonyl}-1-(2- cyclohexylethyl)-D-tryptophan 34 N-{[4-(but-2- 533 3.12 534 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- methoxybenzyl)-D-tryptophan 35 N-{[4-(but-2- 533 2.80 532 [M − H] ynyloxy)phenyl]sulfonyl}-1-(4- methoxybenzyl)-D-tryptophan 36 N-{[4-(but-2- 563 3.12 564 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- dimethoxybenzyl)-D-tryptophan 37 1-(1,3-benzodioxol-5-ylmethyl)-N- 547 2.92 548 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- D-tryptophan 38 N-{[4-(but-2- 587 3.40 588 [M + H] ynyloxy)phenyl]sulfonyl}-1-[4- (trifluoromethoxy)benzyl]-D- tryptophan 39 N-{[4-(but-2- 570 3.37 571 [M + H] ynyloxy)phenyl]sulfonyl}-1-[2- (trifluoromethyl)benzyl]-D- tryptophan 40 N-{[4-(but-2- 570 3.27 569 [M − H] ynyloxy)phenyl]sulfonyl}-1-[3- (trifluoromethyl)benzyl]-D- tryptophan 41 N-{[4-(but-2- 570 3.33 571 [M + H] ynyloxy)phenyl]sulfonyl}-1-[4- (trifluoromethyl)benzyl]-D- tryptophan 42 N-{[4-(but-2- 537 3.56 536 [M − H] ynyloxy)phenyl]sulfonyl}-1-(4- chlorobenzyl)-D-tryptophan 43 N-{[4-(but-2- 528 3.00 529 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- cyanobenzyl)-D-tryptophan 44 N-{[4-(but-2- 528 2.98 529 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- cyanobenzyl)-D-tryptophan 45 N-{[4-(but-2- 528 2.98 529 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- cyanobenzyl)-D-tryptophan 46 5-bromo-N-{[4-(but-2- 491 2.75 490 [M − H] ynyloxy)phenyl]sulfonyl}tryptophan 47 N-{[4-(but-2- 546 2.76 545 [M − H] ynyloxy)phenyl]sulfonyl}-1-(4- methoxybenzyl)-5-methyltryptophan 48 1-benzyl-N-{[4-(but-2- 532 2.90 533 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxytryptophan 49 N-{[4-(but-2- 546 3.02 547 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(2- methylbenzyl)tryptophan 50 N-{[4-(but-2- 546 1.90 547 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(3- methylbenzyl)tryptophan 51 N-{[4-(but-2- 562 1.88 563 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(2- methoxybenzyl)tryptophan 52 N-{[4-(but-2- 562 1.85 563 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(3- methoxybenzyl)tryptophan 53 N-{[4-(but-2- 562 1.85 563 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(4- methoxybenzyl)tryptophan 54 N-{[4-(but-2- 592 1.86 593 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- dimethoxybenzyl)-5- methoxytryptophan 55 N-{[4-(but-2- 600 1.97 601 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-[2- (trifluoromethyl)benzyl]tryptophan 56 N-{[4-(but-2- 600 1.94 601 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-[3- (trifluoromethyl)benzyl]tryptophan 57 N-{[4-(but-2- 600 1.96 601 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-[4- (trifluoromethyl)benzyl]tryptophan 58 N-{[4-(but-2- 550 1.86 551 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- fluorobenzyl)-5-methoxytryptophan 59 N-{[4-(but-2- 550 1.86 551 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- fluorobenzyl)-5-methoxytryptophan 60 N-{[4-(but-2- 550 1.86 551 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- fluorobenzyl)-5-methoxytryptophan 61 N-{[4-(but-2- 568 1.88 569 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- difluorobenzyl)-5- methoxytryptophan 62 N-{[4-(but-2- 567 1.92 568 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- chlorobenzyl)-5-methoxytryptophan 63 N-{[4-(but-2- 574 2.01 575 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- isopropylbenzyl)-5- methoxytryptophan 64 N-{[4-(but-2- 557 1.81 558 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- cyanobenzyl)-5-methoxytryptophan 65 1-(1,3-benzodioxol-5-ylmethyl)-N- 577 1.68 578 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 5-methoxytryptophan 66 N-{[4-(but-2- 534 1.84 535 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(pyridin-3- ylmethyl)tryptophan 67 N-{[4-(but-2- 499 1.87 500 [M + H] ynyloxy)phenyl]sulfonyl}-1-isobutyl- 5-methoxytryptophan 68 N-{[4-(but-2- 513 1.98 514 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-pentyltryptophan 69 N-{[4-(but-2- 511 1.92 512 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclobutylmethyl)-5- methoxytryptophan 70 N-{[4-(but-2- 539 1.98 540 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclohexylmethyl)-5- methoxytryptophan 71 1-benzyl-N-{[4-(but-2- 537 1.97 538 [M + H] ynyloxy)phenyl]sulfonyl}-5- chlorotryptophan 72 N-{[4-(but-2- 551 1.95 552 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (2-methylbenzyl)tryptophan 73 N-{[4-(but-2- 551 1.93 552 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (3-methylbenzyl)tryptophan 74 N-{[4-(but-2- 567 1.93 568 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (2-methoxybenzyl)tryptophan 75 N-{[4-(but-2- 567 2.03 568 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (3-methoxybenzyl)tryptophan 76 N-{[4-(but-2- 567 3.05 568 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-methoxybenzyl)tryptophan 77 N-{[4-(but-2- 605 3.27 606 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- [4- (trifluoromethyl)benzyl]tryptophan 78 N-{[4-(but-2- 621 1.90 622 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- [4- (trifluoromethoxy)benzyl]tryptophan 79 N-{[4-(but-2- 555 1.90 556 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- 2-fluorobenzyl)tryptophan 80 N-{[4-(but-2- 555 2.41 556 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- 3-fluorobenzyl)tryptophan 81 N-{[4-(but-2- 571 2.00 572 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-chlorobenzyl)tryptophan 82 N-{[4-(but-2- 579 3.42 580 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-isopropylbenzyl)tryptophan 83 1-(1,3-benzodioxol-5-ylmethyl)-N- 581 1.83 582 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 5-chlorotryptophan 84 N-{[4-(but-2- 538 1.79 539 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (pyridin-3-ylmethyl)tryptophan 85 N-{[4-(but-2- 503 1.93 504 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- isobutyltryptophan 86 N-{[4-(but-2- 515 1.95 516 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (cyclobutylmethyl)tryptophan 87 N-{[4-(but-2- 543 2.05 544 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (cyclohexylmethyl)tryptophan 88 1-benzyl-N-{[4-(but-2- 551 3.32 552 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-2- methyltryptophan 89 N-{[4-(but-2- 581 3.37 582 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (2-methoxybenzyl)-2- methyltryptophan 90 N-{[4-(but-2- 581 3.32 582 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (3-methoxybenzyl)-2- methyltryptophan 91 N-{[4-(but-2- 581 3.31 582 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-methoxybenzyl)-2- methyltryptophan 92 N-{[4-(but-2- 565 3.43 566 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-2- methyl-1-(4- methylbenzyl)tryptophan 93 N-{[4-(but-2- 619 3.50 620 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-2- methyl-1-[4- (trifluoromethyl)benzyl]tryptophan 94 N-{[4-(but-2- 635 3.54 636 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-2- methyl-1-[4- (trifluoromethoxy)benzyl]tryptophan 95 N-{[4-(but-2- 569 3.32 570 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-fluorobenzyl)-2-methyltryptophan 96 N-{[4-(but-2- 586 3.45 587 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-chlorobenzyl)-2- methyltryptophan 97 N-{[4-(but-2- 593 3.65 594 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-isopropylbenzyl)-2- methyltryptophan 98 N-{[4-(but-2- 576 3.17 577 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (4-cyanobenzyl)-2- methyltryptophan 99 N-{[4-(but-2- 552 2.61 553 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-2- methyl-1-(pyridin-3- ylmethyl)tryptophan 100 1-(1,3-benzodioxol-5-ylmethyl)-N- 595 3.24 596 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 5-chloro-2-methyltryptophan 101 N-{[4-(but-2- 517 3.32 518 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- isobutyl-2-methyltryptophan 102 N-{[4-(but-2- 557 3.63 558 [M + H] ynyloxy)phenyl]sulfonyl}-5-chloro-1- (cyclohexylmethyl)-2- methyltryptophan 103 1-benzyl-N-{[4-(but-2- 547 2.71 546 [M − H] ynyloxy)phenyl]sulfonyl}-5- carboxytryptophan 104 N-{[4-(but-2- 561 2.84 560 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(2-methylbenzyl)tryptophan 105 N-{[4-(but-2- 561 2.84 560 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(3-methylbenzyl)tryptophan 106 N-{[4-(but-2- 561 2.83 560 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-methylbenzyl)tryptophan 107 N-{[(4-(but-2- 577 2.85 576 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(2-methoxybenzyl)tryptophan 108 N-{[4-(but-2- 577 2.67 576 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(3-methoxybenzyl)tryptophan 109 N-{[4-(but-2- 577 2.78 576 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-methoxybenzyl)tryptophan 110 N-{[4-(but-2- 607 2.78 608 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(3,5-dimethoxybenzyl)tryptophan 111 N-{[4-(but-2- 615 3.04 616 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-[2 (trifluoromethyl)benzyl]tryptophan 112 N-{[4-(but-2- 615 2.93 616 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-[3- (trifluoromethyl)benzyl]tryptophan 113 N-{[4-(but-2- 615 3.02 616 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-[4- (trifluoromethyl)benzyl]tryptophan 114 N-{[4-(but-2- 631 3.05 632 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-[4- (trifluoromethoxy)benzyl]tryptophan 115 N-{[4-(but-2- 565 2.75 566 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(2-fluorobenzyl)tryptophan 116 N-{[4-(but-2- 565 2.80 566 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(3-fluorobenzyl)tryptophan 117 N-{[4-(but-2- 565 2.83 566 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-fluorobenzyl)tryptophan 118 N-{[4-(but-2- 583 2.73 584 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(3,5-difluorobenzyl)tryptophan 119 N-{[4-(but-2- 581 2.87 582 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-chlorobenzyl)tryptophan 120 N-{[4-(but-2- 589 3.10 590 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-isopropylbenzyl)tryptophan 121 N-{[4-(but-2- 572 2.38 571 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(2-cyanobenzyl)tryptophan 122 N-{[4-(but-2- 572 2.38 571 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(3-cyanobenzyl)tryptophan 123 N-{[4-(but-2- 572 2.38 571 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-cyanobenzyl)tryptophan 124 1-(1,3-benzodioxol-5-ylmethyl)-N- 591 2.77 590 [M − H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 5-carboxytryptophan 125 N-{[4-(but-2- 548 1.89 549 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(pyridin-3-ylmethyl)tryptophan 126 N-{[4-(but-2- 591 2.37 592 [M + H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(4-carboxybenzyl)tryptophan 127 N-{[4-(but-2- 471 2.25 470 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-methyltryptophan 128 N-{[4-(but-2- 485 2.38 484 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-ethyltryptophan 129 N-{[4-(but-2- 513 2.64 512 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-isobutyltryptophan 130 N-{[4-(but-2- 527 2.80 526 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-pentyltryptophan 131 N-{[4-(but-2- 525 2.60 524 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(cyclobutylmethyl)tryptophan 132 N-{[4-(but-2- 553 2.93 552 [M − H] ynyloxy)phenyl]sulfonyl}-5-carboxy- 1-(cyclohexylmethyl)tryptophan 133 N-{[4-(but-2- 447 1.69 448 [M + H] ynyloxy)phenyl]sulfonyl}-5- chlorotryptophan 134 N-{[4-(but-2- 426 1.62 427 [M + H] ynyloxy)phenyl]sulfonyl}-2- methyltryptophan 135 1-benzyl-N-{[4-(but-2- 527 1.85 528 [M + H] ynyloxy)phenyl]sulfonyl}-5- cyanotryptophan 136 N-{[4-(but-2- 541 2.94 542 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- (4-methylbenzyl)tryptophan 137 N-{[4-(but-2- 557 1.91 558 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- (2-methoxybenzyl)tryptophan 138 N-{[4-(but-2- 557 1.86 558 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- (3-methoxybenzyl)tryptophan 139 N-{[4-(but-2- 557 1.85 558 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- (4-methoxybenzyl)tryptophan 140 N-{[4-(but-2- 611 1.98 612 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- [4- (trifluoromethoxy)benzyl]tryptophan 141 N-{[4-(but-2- 545 1.86 546 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- (4-fluorobenzyl)tryptophan 142 N-{[4-(but-2- 569 2.01 570 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- (4-isopropylbenzyl)tryptophan 143 N-{[4-(but-2- 493 1.84 494 [M + H] ynyloxy)phenyl]sulfonyl}-5-cyano-1- isobutyltryptophan 144 1-benzyl-N-{[4-(but-2- 516 2.54 517 [M + H] ynyloxy)phenyl]sulfonyl}-2- methyltryptophan 145 N-{[4-(but-2- 530 2.57 531 [M + H] ynyloxy)phenyl]sulfonyl}-2-methyl- 1-(2-methylbenzyl)tryptophan 146 N-{[4-(but-2- 546 2.55 547 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- methoxybenzyl)-2-methyltryptophan 147 N-{[4-(but-2- 546 2.53 547 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- methoxybenzyl)-2-methyltryptophan 148 N-{[4-(but-2- 546 2.51 547 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- methoxybenzyl)-2-methyltryptophan 149 N-{[4-(but-2- 584 2.00 585 [M + H] ynyloxy)phenyl]sulfonyl}-2-methyl- 1-[3- (trifluoromethyl)benzyl]tryptophan 150 N-{[4-(but-2- 584 2.61 585 [M + H] ynyloxy)phenyl]sulfonyl}-2-methyl- 1-[4- (trifluoromethyl)benzyl]tryptophan 151 N-{[4-(but-2- 600 2.64 601 [M + H] ynyloxy)phenyl]sulfonyl}-2-methyl- 1-[4- (trifluoromethoxy)benzyl]tryptophan 152 N-{[4-(but-2- 534 2.54 535 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- fluorobenzyl)-2-methyltryptophan 153 N-{[4-(but-2- 534 2.53 535 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- fluorobenzyl)-2-methyltryptophan 154 N-{[4-(but-2- 534 2.53 535 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- fluorobenzyl)-2-methyltryptophan 155 N-{[4-(but-2- 552 2.55 553 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- difluorobenzyl)-2-methyltryptophan 156 N-{[4-(but-2- 550 2.61 551 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- chlorobenzyl)-2-methyltryptophan 157 N-{[4-(but-2- 558 2.70 559 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- isopropylbenzyl)-2- methyltryptophan 158 N-{[4-(but-2- 541 2.23 542 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- cyanobenzyl)-2-methyltryptophan 159 N-{[4-(but-2- 541 2.25 542 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- cyanobenzyl)-2-methyltryptophan 160 N-{[4-(but-2- 541 2.23 542 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- cyanobenzyl)-2-methyltryptophan 161 1-(1,3-benzodioxol-5-ylmethyl)-N- 560 2.49 561 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 2-methyltryptophan 162 N-{[4-(but-2- 517 2.10 518 [M + H] ynyloxy)phenyl]sulfonyl}-2-methyl- 1-(pyridin-3-ylmethyl)tryptophan 163 N-{[4-(but-2- 454 2.40 455 [M + H] ynyloxy)phenyl]sulfonyl}-1-ethyl-2- methyltryptophan 164 N-{[4-(but-2- 482 2.53 483 [M + H] ynyloxy)phenyl]sulfonyl}-1-isobutyl- 2-methyltryptophan 165 N-{[4-(but-2- 494 2.56 495 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclobutylmethyl)-2- methyltryptophan 166 N-{[4-(but-2- 522 3.34 523 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclohexylmethyl)-2- methyltryptophan 167 1-benzyl-N-{[4-(but-2- 516 2.54 517 [M + H] ynyloxy)phenyl]sulfonyl}-5- methyltryptophan 168 N-{[4-(but-2- 530 2.59 531 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-(2-methylbenzyl)tryptophan 169 N-{[4-(but-2- 530 3.18 531 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-(3-methylbenzyl)tryptophan 170 N-{[4-(but-2- 546 2.57 547 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- methoxybenzyl)-5-methyltryptophan 171 N-{[4-(but-2- 546 2.54 547 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- methoxybenzyl)-5-methyltryptophan 172 N-{[4-(but-2- 584 2.65 585 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-[2- (trifluoromethyl)benzyl]tryptophan 173 N-{[4-(but-2- 584 2.61 585 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-[3- (trifluoromethyl)benzyl]tryptophan 174 N-{[4-(but-2- 584 2.62 585 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-[4- (trifluoromethyl)benzyl]tryptophan 175 N-{[4-(but-2- 534 2.55 535 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- fluorobenzyl)-5-methyltryptophan 176 N-{[4-(but-2- 534 2.55 535 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- fluorobenzyl)-5-methyltryptophan 177 N-{[4-(but-2- 552 2.56 553 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- difluorobenzyl)-5-methyltryptophan 178 N-{[4-(but-2- 551 2.61 552 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- chlorobenzyl)-5-methyltryptophan 179 N-{[4-(but-2- 558 2.71 559 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- isopropylbenzyl)-5- methyltryptophan 180 1-(1,3-benzodioxol-5-ylmethyl)-N- 560 2.51 561 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 5-methyltryptophan 181 N-{[4-(but-2- 517 2.15 518 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-(pyridin-3-ylmethyl)tryptophan 182 N-{[4-(but-2- 454 2.82 455 [M + H] ynyloxy)phenyl]sulfonyl}-1-ethyl-5- methyltryptophan 183 N-{[4-(but-2- 482 2.56 483 [M + H] ynyloxy)phenyl]sulfonyl}-1-isobutyl- 5-methyltryptophan 184 N-{[4-(but-2- 496 2.64 497 [M + H] ynyloxy)phenyl]sulfonyl}-5-methyl- 1-pentyltryptophan 185 1-benzyl-N-{[4-(but-2- 547 3.13 548 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyltryptophan 186 N-{[4-(but-2- 561 3.23 562 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-(2- methylbenzyl)tryptophan 187 N-{[4-(but-2- 561 3.24 562 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-(3- methylbenzyl)tryptophan 188 N-{[4-(but-2- 561 3.25 562 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-(4- methylbenzyl)tryptophan 189 N-{[4-(but-2- 577 3.18 578 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(2-methoxybenzyl)-2- methyltryptophan 190 N-{[4-(but-2- 577 3.11 578 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(3-methoxybenzyl)-2- methyltryptophan 191 N-{[4-(but-2- 577 3.10 578 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1-(4-methoxybenzyl)-2- methyltryptophan 192 N-{[4-(but-2- 607 3.11 608 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- dimethoxybenzyl)-5-methoxy-2- methyltryptophan 193 N-{[4-(but-2- 615 3.38 616 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-[2- (trifluoromethyl)benzyl]tryptophan 194 N-{[4-(but-2- 631 3.37 632 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-[3- (trifluoromethoxy)benzyl]tryptophan 195 N-{[4-(but-2- 615 3.33 616 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-[4- (trifluoromethyl)benzyl]tryptophan 196 N-{[4-(but-2- 631 3.40 632 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1-[4- (trifluoromethoxy)benzyl]tryptophan 197 N-{[4-(but-2- 565 3.16 566 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- fluorobenzyl)-5-methoxy-2- methyltryptophan 198 N-{[4-(but-2- 565 3.14 566 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- fluorobenzyl)-5-methoxy-2- methyltryptophan 199 N-{[4-(but-2- 565 3.15 566 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- fluorobenzyl)-5-methoxy-2- methyltryptophan 200 N-{[4-(but-2- 583 3.10 584 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3,5- difluorobenzyl)-5-methoxy-2- methyltryptophan 201 N-{[4-(but-2- 581 3.19 582 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- chlorobenzyl)-5-methoxy-2- methyltryptophan 202 N-{[4-(but-2- 589 3.39 590 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- isopropylbenzyl)-5-methoxy-2- methyltryptophan 203 N-{[4-(but-2- 572 2.93 573 [M + H] ynyloxy)phenyl]sulfonyl}-1-(2- cyanobenzyl)-5-methoxy-2- methyltryptophan 204 N-{[4-(but-2- 572 2.88 573 [M + H] ynyloxy)phenyl]sulfonyl}-1-(3- cyanobenzyl)-5-methoxy-2- methyltryptophan 205 N-{[4-(but-2- 572 2.88 573 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- cyanobenzyl)-5-methoxy-2- methyltryptophan 206 1-(1,3-benzodioxol-5-ylmethyl)-N- 591 3.05 592 [M + H] {[4-(but-2-ynyloxy)phenyl]sulfonyl}- 5-methoxy-2-methyltryptophan 207 N-{[4-(but-2- 591 2.64 592 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- carboxybenzyl)-5-methoxy-2- methyltryptophan 208 N-{[4-(but-2- 471 2.66 472 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-1,2-dimethyltryptophan 209 N-{[4-(but-2- 485 2.76 486 [M + H] ynyloxy)phenyl]sulfonyl}-1-ethyl-5- methoxy-2-methyltryptophan 210 N-{[4-(but-2- 513 3.04 514 [M + H] ynyloxy)phenyl]sulfonyl}-1-isobutyl- 5-methoxy-2-methyltryptophan 211 N-{[4-(but-2- 527 3.21 528 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-2-methyl-1- pentyltryptophan 212 N-{[4-(but-2- 525 3.10 526 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclobutylmethyl)-5-methoxy-2- methyltryptophan 213 N-{[4-(but-2- 553 3.34 554 [M + H] ynyloxy)phenyl]sulfonyl}-1- (cyclohexylmethyl)-5-methoxy-2- methyltryptophan 214 N-{[4-(but-2- 518 2.38 517 [M − H] ynyloxy)phenyl]sulfonyl}-1-(4- hydroxybenzyl)-D-tryptophan 215 N-{[4-(but-2- 546 2.54 547 [M + H] ynyloxy)phenyl]sulfonyl}-1-(4- ethoxybenzyl)-D-tryptophan 216 1-[4-(allyloxy)benzyl]-N-{[4-(but-2- 558 3.08 559 [M + H] ynyloxy)phenyl]sulfonyl}-D- tryptophan 217 N-{[4-(but-2- 426 2.69 427 [M + H] ynyloxy)phenyl]sulfonyl}-5-meth- D(or L)-tryptophan 218 N-{[4-(but-2- 426 2.69 427 [M + H] ynyloxy)phenyl]sulfonyl}-5- methyl(or D)-L-tryptophan 219 1-(tert-butoxycarbonyl)-N-{[4-(but-2- 513 3.05 512 [M − H] ynyloxy)phenyl]sulfonyl}-L- tryptophan 220 1-(tert-butoxycarbonyl)-N-{[4-(but-2- 513 3.06 512 [M − H] ynyloxy)phenyl]sulfonyl}-D- tryptophan 221 N-{[4-(but-2- 442 2.50 443 [M + H] ynyloxy)phenyl]sulfonyl}-5- methoxy-D(or L)-tryptophan 222 N-{[4-(but-2- 442 2.51 443 [M + H] ynyloxy)phenyl]sulfonyl}-methoxy- L(or D)-tryptophan 223 5-(benzyloxy)-N-{[4-(but-2- 519 2.99 520 [M + H] ynyloxy)phenyl]sulfonyl}-D(or L)- tryptophan 224 5-(benzyloxy)-N-{[4-(but-2- 519 2.98 520 [M + H] ynyloxy)phenyl]sulfonyl}-L(or D)- tryptophan Exemplary Syntheses of Compounds of the Invention

Procedures for the preparation of compounds of Examples 4, 6, 20, 32, 39, 46 and 47 are shown below.

Preparation of Compound of Example 6 2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)-3-(5-METHYL-1H-INDOL-3-YL)-PROPIONIC ACID

Step 1:

Triethylamine (0.38 mL, 2.75 mmol) was added to a solution of 5-methyl-DL-tryptophan (0.20 g, 0.92 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (0.25 g, 1.01 mmol) in H₂O-dioxane (1.6 mL/2.4 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was then concentrated and acidified with HCl. The mixture was extracted with ethyl acetate (3×10 mL). The organic solution was washed with H₂O and brine, dried over Na₂SO₄, and concentrated. The residue was purified by RP-HPLC to give 0.32 g (81%) of the title compound as a pale yellow solid. Mp=45-46° C.; ¹H NMR (DMSO-d₆): 400 MHz δ 12.54 (bs, 1H), 10.64 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.53 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.00 (m, 2H), 6.95 (m, 2H), 6.86 (dd J=8.0, 4.0 Hz, 1H), 4.78 (q, J=2.4 Hz, 2H), 3.81 (q, J=7.6 Hz, 1H), 3.00 (dd J=14.4, 6.8 Hz, 1H), 2.79 (dd J=14.4, 7.8 Hz, 1H), 2.33 (s, 3H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C₂₂H₂₃N₂O₅S (ESI+, [M+H]¹⁺), 427.1322; found 427.1327; LCMS m/z (ESI) [M+H]¹⁺ 427, retention time=2.69 min.

Step 2: Chiral Separation

Preparative HPLC using CHIRALPAK®-OD™ (20×250 mm) (Chiral Technologies, Inc., Westchester, Pa., USA) and 15% isopropyl alcohol in heptane (0.02% TFA) as eluant (instrument: JAI-908, flow rate: 19 mL/min) gave D and L enantiomers as a white solid. Analytical chiral HPLC using CHIRALCEL®-OD™ (4.6×250 mm) (Chiral Technologies, Inc., Westchester, Pa., USA) and ethanol/heptane (containing 0.02% TFA) at 13:87, 1.0 mL/min, 225 nm, gave: retention time (T_(R)): 23.0 min (1^(st) peak) and 26.2 min (2^(nd) peak). The stereochemistry of the two enantiomers was not determined.

Preparation of Compound of Example 4 2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)-3-(5-METHOXY-1H-INDOL-3-YL)-PROPIONIC ACID

Step 1:

The title compound was prepared by the method of Example 6, using 5-methoxy-DL-tryptophan and 4-but-2-ynyloxy-benzenesulfonyl chloride as starting materials. ¹H NMR (DMSO-d₆): 400 MHz δ12.55 (bs, 1H), 10.63 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 2H), 6.82 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.0, 2.0 Hz, 1H), 4.78 (q, J=2.0 Hz, 2H), 3.87 (q, J=7.6 Hz, 1H), 3.72 (s, 3H), 3.00 (dd J=14.4, 6.4 Hz, 1H), 2.82 (dd J=14.4, 7.6 Hz, 1H), 1.83 (t, J=2.0 Hz, 3H); HRMS: calcd for C₂₂H₂₄N₂O₆S (ESI+, [M+H]¹⁺), 443.1271; found 443.1265; LCMS m/z (ESI) [M+H] 443, retention time=2.50 min.

Step 2: Chiral Separation

Preparative HPLC using CHIRALPAK®-OJ™ (20×250 mm) (Chiral Technologies, Inc., Westchester, Pa., USA) and 15% ethanol in heptane (0.1% TFA) as eluant (flow rate: 7 mL/min) gave D and L enantiomers as a white solid. Analytical chiral HPLC using CHIRALCEL®-OJ™ (4.6×250 mm) (Chiral Technologies, Inc., Westchester, Pa., USA) and ethanol/heptane (containing 0.02% TFA) at 85:15, 1.0 mL/min, 215 nm, gave: retention time (T_(R)): 4.86 min (1^(st) peak) and 6.32 min (2^(nd) peak). The stereochemistry of the two enantiomers was not determined.

Preparation of Compound of Example 20 2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)-3-(5-BENZYLOXY-1H-INDOL-3-YL)-PROPIONIC ACID

Step 1:

The title compound was prepared by the method of Example 6, using 5-benzyloxy-DL-tryptophan and 4-but-2-ynyloxy-benzenesulfonyl chloride as starting materials. ¹H NMR (DMSO-d₆): 400 MHz δ 12.55 (bs, 1H), 10.64 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.50-7.33 (m, 7H), 7.19 (d, J=12.0 Hz, 1H), 7.03 (d, J=4.0 Hz, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.76 (dd, J=8.0, 4.0 Hz, 1H), 5.04 (s, 2H), 4.74 (q, J=2.4 Hz, 2H), 3.86 (q, J=8.0 Hz, 1H), 3.00 (dd J=14.4, 6.4 Hz, 1H), 2.83 (dd J=14.4, 8.0 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C₂₈H₂₇N₂O₆S (ESI+, [M+H]¹⁺), 519.1584; found 519.1588; LCMS m/z (ESI) [M+H] 519, retention time=2.99 min.

Step 2: Chiral Separation

Preparative HPLC using CHIRALPAK®-OJ™ (20×250 mm) (Chiral Technologies, Inc., Westchester, Pa., USA) and 15% ethanol in heptane (0.1% TFA) as eluant (flow rate: 13 mL/min) gave D and L enantiomers as a white solid. Analytical chiral HPLC using CHIRALCEL®-OJ™ (4.6×250 mm) (Chiral Technologies, Inc., Westchester, Pa., USA) and ethanol/heptane (containing 0.02% TFA) at 85:15, 1.0 mL/min, 215 nm, gave: retention time (T_(R)): 6.76 min (1^(st) peak) and 13.1 min (2^(nd) peak). The stereochemistry of the two enantiomers was not determined.

Preparation of Compound of Example 32 2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)-3-(1-CYCLOBUTYLMETHYL-1H-INDOL-3-YL)-PROPIONIC ACID

Step 1: Synthesis of N-(tert-butoxycarbonyl)-1-cyclobutylmethyl-D-tryptophan

In a 20 mL vial, NaH (60% in mineral oil) (0.092 g, 2.30 mmol) was added to a solution of N-(tert-butoxycarbonyl)-D-tryptophan (0.200 g, 0.657 mmol) in anhydrous N,N-dimethylformamide (4 mL) at 0° C. The reaction mixture was placed in a shaker for 20 min. at 0° C. (Bromomethyl)cyclobutane (0.074 mL, 0.657 mmol) was added to the solution and allowed to react for 10 hours at 0° C. The reaction mixture was quenched with H₂O and acidified with 1M NaHSO₄ until pH=3. The solution was extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, and concentrated to give the title compound.

Step 2: Synthesis of 1-cyclobutylmethyl-D-tryptophan

The dried crude product of Step 1 was dissolved in CH₂Cl₂-TFA (1 mL/1 mL) and the solution was shaken for 10 hours at room temperature. The solution was concentrated and the resulting product was dissolved in CH₂Cl₂. The solution was washed with H₂O and brine, dried over Na₂SO₄, and concentrated to give the title compound.

Step 3: Synthesis of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-(1-cyclobutylmethyl-1H-indol-3-yl)-propionic acid

Triethylamine (0.275 mL, 1.97 mmol) was added to a solution of crude 1-cyclobutylmethyl-D-tryptophan of Step 2 (0.657 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (0.177 g, 0.723 mmol) in H₂O-dioxane (2 mL:3 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was then concentrated and acidified with HCl. The mixture was extracted with ethyl acetate (3×10 mL). The organic solution was washed with H₂O and brine, dried over Na₂SO₄, and concentrated. The residue was purified by RP-HPLC to give 0.152 g (48% in 3 steps) of the title compound as a yellow solid. ¹H NMR (DMSO-d₆): 400 MHz δ 12.57 (bs, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 7.02 (s, 1H), 6.96-6.88 (m, 3H), 4.77 (q, J=2.4 Hz, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.84 (q, J=6.8 Hz, 1H), 3.02 (dd J=14.4, 6.4 Hz, 1H), 2.82 (dd J=14.4, 8.4 Hz, 1H), 2.67 (p, J=7.6 Hz, 1H), 1.91 (m, 2H), 1.83 (m, 5H), 1.75 (m, 2H); HRMS: calcd for C₂₆H₂₉N₂O₅S (ESI+, [M+H]¹⁺), 481.1792; found 481.1786; LCMS m/z (ESI) [M+H] 481, retention time=3.22 min.

Preparation of Compound of Example 39 2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)-3-[1-(2-TRIFLUOROMETHYLBENZYL)-1H-INDOL-3-YL]-PROPIONIC ACID

The title compound was prepared by the method of Example 32, using N-(tert-butoxycarbonyl)-D-tryptophan and 2-(trifluoromethyl)benzyl bromide as starting materials. ¹H NMR (DMSO-d₆): 400 MHz δ 12.57 (bs, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.43 (m, 2H), 7.37 (d, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.12-6.99 (m, 3H), 6.93 (d, J=8.8 Hz, 2H), 6.44 (d, J=6.4 Hz, 1H), 5.51 (s, 2H), 4.77 (q, J=2.0 Hz, 2H), 3.91 (q, J=7.6 Hz, 1H), 3.08 (dd J=14.4, 7.2 Hz, 1H), 2.88 (dd J=14.4, 7.6 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C₂₉H₂₆F₃N₂O₅S (ESI+, [M+H]¹⁺), 571.1509; found 571.1505; LCMS m/z (ESI) [M+H] 571, retention time=3.37 min.

Preparation of Compound of Example 46 3-(5-BROMO-1H-INDOL-3-YL)-2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)—PROPIONIC ACID

Step 1: Synthesis of 3-bromo-2-hydroxyimino-propionic acid ethyl ester

Gilchrist, T. L. and T. G Roberts, J. Chem, Soc. Perkin Trans 1, 1983, 1283-1292, is incorporated herein by reference in its entirety.

A solution of hydroxylamine sulfate (5.00 g, 31 mmol) in water (30 mL) was added to a solution of ethylbrompyruvate (90%) (6.50 g, 30 mmol) in CHCl₃ (10 mL). The two-phase system was rapidly stirred for 24 hours at room temperature. The mixture was extracted with CHCl₃ (3×30 mL). The combined extracts were dried over Na₂SO₄ and concentrated to give 7.00 g of the title compound as a white solid. ¹H NMR (CDCl₃): 300 MHz δ 10.08 (bs, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.27 (s, 2H), 1.39 (t, J=7.2 Hz, 3H).

Step 2: Synthesis of 2-hydroxyimino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester

A solution of 3-bromo-2-hydroxyimino-propionic acid ethyl ester (3.21 g, 15.3 mmol) in CH₂Cl₂ (20 mL) was slowly added dropwise to a stirring mixture of 5-bromoindole (3.0 g, 15.3 mmol) and Na₂CO₃ (8.92 g, 84.2 mmol) in CH₂Cl₂ (30 mL) at room temperature. The mixture was stirred for 20 hours, filtered through CELITE® and concentrated to give 4.94 g of the title compound as a crude material. LCMS m/z (ESI) [M+H]⁺ calcd for C₁₋₃H₁₄BrN₂O₃ (Br⁷⁹) 325.2, found 325.2.

Step 3: Synthesis of 2-amino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester

Zinc dust (3.30 g, 50.4 mmol) was added portionwise to a stirred solution of 2-hydroxyimino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (4.10 g, 12.61 mmol) in acetic acid (100 mL) over 30 min. After stirring overnight, the mixture was filtered through CELITE® and concentrated. The residue was dissolved in 1 N HCl and re-evaporated to give 4.30 g of the title compound as a crude material. LCMS m/z (ESI) [M-HCl+H]+calcd for C₁₋₃H₁₅BrN₂O₂ (Br⁷⁹) 312.2, found 312.2.

Step 4: Synthesis of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester

Triethylamine (4.81 mL, 34.5 mmol) was added to a mixture of 2-amino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (4.00 g, 11.51 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (3.10 g, 12.66 mmol) in H₂O-dioxane (40 mL/60 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was concentrated and diluted with ethyl acetate. The organic solution was washed with H₂O and brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (silica, 40% ethyl acetate in hexanes) to give 3.67 g of the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆): 400 MHz δ 11.05 (s, 1H), 8.31 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.45 (d, J=1.6 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.80 (q, J=2.4 Hz, 2H), 3.88 (q, J=7.6 Hz, 1H), 3.75 (q, J=7.2 Hz, 2H), 3.00 (dd J=14.4, 7.2 Hz, 1H), 2.88 (dd J=14.4, 7.6 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H); HRMS: calcd for C₂₃H₂₄BrN₂O₅S (ESI+, Br⁷⁹, [M+H]¹⁺), 519.0584; found 519.0589.

Step 5: Synthesis of 3-(5-bromo-1H-indol-3-yl)-2-(4-but-2-ynyloxy-benzenesulfonyl amino)-propionic acid

2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (0.100 g, 0.193 mmol) was dissolved in 0.5 mL tetrahydrofuran. To the solution was added MeOH (0.5 mL) and 1 N NaOH (0.4 mL, 0.4 mmol). The reaction mixture was placed in a shaker for 10 hours at room temperature. The solution was acidified with 1N HCl and extracted with ethyl acetate (3×3 mL). The organic solution was concentrated and the residue was purified by RP-HPLC to give 0.089 g (94%) of the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆): 400 MHz δ 12.65 (bs, 1H), 11.01 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.48 (m, 3H), 7.26 (d, J=8.8 Hz, 1H), 7.13 (m, 2H), 6.89 (d, J=9.2 Hz, 2H), 4.77 (q, J=2.8 Hz, 2H), 3.82 (q, J=8.4 Hz, 1H), 3.01 (dd J=14.6, 6.4 Hz, 1H), 2.82 (dd J=14.6, 8.0 Hz, 1H), 1.83 (t, J=2.4 Hz, 3H); HRMS: calcd for C₂₁H₂₀BrN₂O₅S (ESI+, Br⁷⁹, [M+H]¹⁺), 491.0271; found 491.0287; LCMS m/z (ESI) [M−H] 489 (Br⁷⁹), retention time=2.75 min.

Preparation of Compound of Example 47 2-(4-BUT-2-YNYLOXY-BENZENESULFONYLAMINO)-3-[1-(4-METHOXY-BENZYL)-5-METHYL-1H-INDOL-3-YL]-PROPIONIC ACID

In a 20 mL vial, NaH (60% in mineral oil) (0.033 g, 0.831 mmol) was added to a solution of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-(5-methyl-1H-indol-3-yl)-propionic acid (Example 1) (0.100 g, 0.234 mmol) in anhydrous N,N-dimethylformamide (2 mL) at 0° C. The reaction mixture was placed in a shaker for 20 min. at 0° C. 4-Methoxy-benzyl chloride (0.032 mL, 0.234 mmol) was added to the solution and allowed to react for 10 hours at 0° C. The reaction mixture was quenched with H₂O and acidified with HCl. The solution was extracted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄, and concentrated. The residue was purified by RP-HPLC to give 0.086 g (67%) of the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆): 400 MHz δ 12.58 (bs, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.53 (d, J=11.6 Hz, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.00 (s, 1H), 6.92-6.80 (m, 5H), 5.17 (s, 2H), 4.76 (q, J=2.4 Hz, 2H), 3.82 (q, J=8.0 Hz, 1H), 3.69 (s, 3H), 3.00 (dd J=14.4, 6.8 Hz, 1H), 2.79 (dd J=14.4, 7.6 Hz, 1H), 2.32 (s, 3H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C₃₀H₃₁N₂O₆S (ESI+, [M+H]¹⁺), 547.1897; found 547.1896; LCMS m/z (ESI) [M−H] 545, retention time=2.76 min.

The following compounds were prepared according to the procedures of the Synthetic Procedures described above, using the starting materials (SM1/SM2) as described in the Table below. Prepared by using same SM2 synthetic SM1 (alkyl halide, procedures of (indole or N/A = not Example Compound Name Example # tryptophan) applicable) 1 N-{[4-(but-2- 6 (step 1) D-tryptophan N/A ynyloxy)phenyl]sulfonyl}- D-tryptophan 2 N-{[4-(but-2- 6 (step 1) L-tryptophan N/A ynyloxy)phenyl]sulfonyl}-L- tryptophan 3 N-{[4-(but-2- 6 (step 1) 5-fluorotryptophan N/A ynyloxy)phenyl]sulfonyl}-5- fluorotryptophan 4 N-{[4-(but-2- 6 (step 1) 5-methoxytryptophan N/A ynyloxy)phenyl]sulfonyl}-5- methoxytryptophan 5 N-{[4-(but-2- 6 (step 1) 5-hydroxytryptophan N/A ynyloxy)phenyl]sulfonyl}-5- hydroxytryptophan 6 N-{[4-(but-2- 6 (step 1) 5-methyltryptophan N/A ynyloxy)phenyl]sulfonyl}-5- methyltryptophan 7 N-{[4-(but-2- 6 (step 1) 6-fluorotryptophan N/A ynyloxy)phenyl]sulfonyl}-6- fluorotryptophan 8 N-{[4-(but-2- 6 (step 1) 6-methyltryptophan N/A ynyloxy)phenyl]sulfonyl}-6- methyltryptophan 9 N-{[4-(but-2- 6 (step 1) alpha-methyltryptophan N/A ynyloxy)phenyl]sulfonyl}- alpha-methyltryptophan 10 N-{[4-(but-2- 6 (step 1) 7-methyltryptophan N/A ynyloxy)phenyl]sulfonyl}-7- methyltryptophan 11 N-{[4-(but-2- 6 (step 1) 5-hydroxy-L- N/A ynyloxy)phenyl]sulfonyl}-5- tryptophan hydroxy-L-tryptophan 12 N-{[4-(but-2- 32 L-tryptophan n-propyl bromide ynyloxy)phenyl]sulfonyl}-1- propyl-L-tryptophan 13 1-butyl-N-{[4-(but-2- 32 L-tryptophan n-butyl bromide ynyloxy)phenyl]sulfonyl}-L- tryptophan 14 N-{[4-(but-2- 32 L-tryptophan 2-methylpropylbromide ynyloxy)phenyl]sulfonyl}-1- isobutyl-L-tryptophan 15 1-allyl-N-{[4-(but-2- 32 L-tryptophan allyl bromide ynyloxy)phenyl]sulfonyl}-L- tryptophan 16 N-{[4-(but-2- 32 L-tryptophan 3-methylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-methylbenzyl)-L- tryptophan 17 N-{[4-(but-2- 32 L-tryptophan 4-methylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-methylbenzyl)-L- tryptophan 18 N-{[4-(but-2- 32 L-tryptophan 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-chlorobenzyl)-L- tryptophan 19 N-{[4-(but-2- 32 L-tryptophan 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-methoxybenzyl)-L- tryptophan 20 5-(benzyloxy)-N-{[4-(but-2- 20 5-benzyloxy-D/L- N/A ynyloxy)phenyl]sulfonyl}tryptophan tryptophan 21 N-{[4-(but-2- 32 D-tryptophan iodomethane ynyloxy)phenyl]sulfonyl}-1- methyl-D-tryptophan 22 N-{[4-(but-2- 32 D-tryptophan 1-bromo-pentane ynyloxy)phenyl]sulfonyl}-1- pentyl-D-tryptophan 23 N-{[4-(but-2- 32 D-tryptophan bromomethyl ynyloxy)phenyl]sulfonyl}-1- cyclohexane (cyclohexylmethyl)-D- tryptophan 24 N-{[4-(but-2- 32 D-tryptophan 4-phenoxybutyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-phenoxybutyl)-D- tryptophan 25 1-benzyl-N-{[4-(but-2- 32 D-tryptophan benzyl bromide ynyloxy)phenyl]sulfonyl}- D-tryptophan 26 N-{[4-(but-2- 32 D-tryptophan 4-methylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-methylbenzyl)-D- tryptophan 27 1-(1,1′-biphenyl-2- 32 D-tryptophan 2-phenylbenzyl ylmethyl)-N-{[4-(but-2- bromide ynyloxy)phenyl]sulfonyl}- D-tryptophan 28 N-{[4-(but-2- 32 D-tryptophan 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-fluorobenzyl)-D- tryptophan 29 N-{[4-(but-2- 32 D-tryptophan 2-bromethyl ynyloxy)phenyl]sulfonyl}-1- naphthalene (2-naphthylmethyl)-D- tryptophan 30 N-{[4-(but-2- 32 D-tryptophan 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-1- pyridine (pyridin-3-ylmethyl)-D- tryptophan 31 N-{[4-(but-2- 32 D-tryptophan bromethylcyclo ynyloxy)phenyl]sulfonyl}-1- propane (cyclopropylmethyl)-D- tryptophan 32 N-{[4-(but-2- 32 D-tryptophan bromethylcyclo ynyloxy)phenyl]sulfonyl}-1- butane (cyclobutylmethyl)-D- tryptophan 33 N-{[4-(but-2- 32 D-tryptophan 1-bromo-2- ynyloxy)phenyl]sulfonyl}-1- cyclohexylethane (2-cyclohexylethyl)-D- tryptophan 34 N-{[4-(but-2- 32 D-tryptophan 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- chloride (3-methoxybenzyl)-D- tryptophan 35 N-{[4-(but-2- 32 D-tryptophan 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- chloride (4-methoxybenzyl)-D- tryptophan 36 N-{[4-(but-2- 32 D-tryptophan 3,5- ynyloxy)phenyl]sulfonyl}-1- dimethoxybenzyl (3,5-dimethoxybenzyl)-D- chloride tryptophan 37 1-(1,3-benzodioxol-5- 32 D-tryptophan 3,4-methylene ylmethyl)-N-{[4-(but-2- dioxybenzyl ynyloxy)phenyl]sulfonyl}- chloride D-tryptophan 38 N-{[4-(but-2- 32 D-tryptophan 4-trifluoromethoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide [4- (trifluoromethoxy)benzyl]- D-tryptophan 39 N-{[4-(but-2- 32 D-tryptophan 2-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide [2-(trifluoromethyl)benzyl]- D-tryptophan 40 N-{[4-(but-2- 32 D-tryptophan 3-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide [3-(trifluoromethyl)benzyl]- D-tryptophan 41 N-{[4-(but-2- 32 D-tryptophan 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide [4-(trifluoromethyl)benzyl]- D-tryptophan 42 N-{[4-(but-2- 32 D-tryptophan 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-1- chloride (4-chlorobenzyl)-D- tryptophan 43 N-{[4-(but-2- 32 D-tryptophan 2-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-cyanobenzyl)-D- tryptophan 44 N-{[4-(but-2- 32 D-tryptophan 3-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-cyanobenzyl)-D- tryptophan 45 N-{[4-(but-2- 32 D-tryptophan 4-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-cyanobenzyl)-D- tryptophan 46 5-bromo-N-{[4-(but-2- 46 5-methylindole N/A ynyloxy)phenyl]sulfonyl}tryptophan 47 N-{[4-(but-2- 47 5-methylindole 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-methoxybenzyl)-5- methyltryptophan 48 1-benzyl-N-{[4-(but-2- 46 and 47 5-methoxyindole benzyl bromide ynyloxy)phenyl]sulfonyl}-5- methoxytryptophan 49 N-{[4-(but-2- 46 and 47 5-methoxyindole 2-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methoxy-1-(2- methylbenzyl)tryptophan 50 N-{[4-(but-2- 46 and 47 5-methoxyindole 3-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methoxy-1-(3- methylbenzyl)tryptophan 51 N-{[4-(but-2- 46 and 47 5-methoxyindole 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methoxy-1-(2- methoxybenzyl)tryptophan 52 N-{[4-(but-2- 46 and 47 5-methoxyindole 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methoxy-1-(3- methoxybenzyl)tryptophan 53 N-{[4-(but-2- 46 and 47 5-methoxyindole 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methoxy-1-(4- methoxybenzyl)tryptophan 54 N-{[4-(but-2- 46 and 47 5-methoxyindole 3,5- ynyloxy)phenyl]sulfonyl}-1- dimethoxybenzyl (3,5-dimethoxybenzyl)-5- bromide methoxytryptophan 55 N-{[4-(but-2- 46 and 47 5-methoxyindole 2- ynyloxy)phenyl]sulfonyl}-5- trifluoromethylbenzyl methoxy-1-[2- bromide (trifluoromethyl)benzyl]tryptophan 56 N-{[4-(but-2- 46 and 47 5-methoxyindole 3- ynyloxy)phenyl]sulfonyl}-5- trifluoromethylbenzyl methoxy-1-[3- bromide (trifluoromethyl)benzyl]tryptophan 57 N-{[4-(but-2- 46 and 47 5-methoxyindole 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methoxy-1-[4- (trifluoromethyl)benzyl]tryptophan 58 N-{[4-(but-2- 46 and 47 5-methoxyindole 2-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-fluorobenzyl)-5- methoxytryptophan 59 N-{[4-(but-2- 46 and 47 5-methoxyindole 3-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-fluorobenzyl)-5- methoxytryptophan 60 N-{[4-(but-2- 46 and 47 5-methoxyindole 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-fluorobenzyl)-5- methoxytryptophan 61 N-{[4-(but-2- 46 and 47 5-methoxyindole 3,5-difluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3,5-difluorobenzyl)-5- methoxytryptophan 62 N-{[4-(but-2- 46 and 47 5-methoxyindole 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-chlorobenzyl)-5- methoxytryptophan 63 N-{[4-(but-2- 46 and 47 5-methoxyindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-isopropylbenzyl)-5- methoxytryptophan 64 N-{[4-(but-2- 46 and 47 5-methoxyindole 2-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-cyanobenzyl)-5- methoxytryptophan 65 1-(1,3-benzodioxol-5- 46 and 47 5-methoxyindole 5-bromomethyl- ylmethyl)-N-{[4-(but-2- benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-5- methoxytryptophan 66 N-{[4-(but-2- 46 and 47 5-methoxyindole 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-5- pyridine methoxy-1-(pyridin-3- ylmethyl)tryptophan 67 N-{[4-(but-2- 46 and 47 5-methoxyindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide isobutyl-5- methoxytryptophan 68 N-{[4-(but-2- 46 and 47 5-methoxyindole 1-bromo-pentane ynyloxy)phenyl]sulfonyl}-5- methoxy-1- pentyltryptophan 69 N-{[4-(but-2- 46 and 47 5-methoxyindole bromomethyl- ynyloxy)phenyl]sulfonyl}-1- cyclobutane (cyclobutylmethyl)-5- methoxytryptophan 70 N-{[4-(but-2- 46 and 47 5-methoxyindole bromomethyl- ynyloxy)phenyl]sulfonyl}-1- cyclohexane (cyclohexylmethyl)-5- methoxytryptophan 71 1-benzyl-N-{[4-(but-2- 46 and 47 5-chloroindole benzyl bromide ynyloxy)phenyl]sulfonyl}-5- chlorotryptophan 72 N-{[4-(but-2- 46 and 47 5-chloroindole 2-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(2- methylbenzyl)tryptophan 73 N-{[4-(but-2- 46 and 47 5-chloroindole 3-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(3- methylbenzyl)tryptophan 74 N-{[4-(but-2- 46 and 47 5-chloroindole 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(2- methoxybenzyl)tryptophan 75 N-{[4-(but-2- 46 and 47 5-chloroindole 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(3- methoxybenzyl)tryptophan 76 N-{[4-(but-2- 46 and 47 5-chloroindole 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(4- methoxybenzyl)tryptophan 77 N-{[4-(but-2- 46 and 47 5-chloroindole 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-[4- (trifluoromethyl)benzyl]tryptophan 78 N-{[4-(but-2- 46 and 47 5-chloroindole 4-trifluoromethoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-[4- (trifluoromethoxy)benzyl]tryptophan 79 N-{[4-(but-2- 46 and 47 5-chloroindole 2-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(2- fluorobenzyl)tryptophan 80 N-{[4-(but-2- 46 and 47 5-chloroindole 3-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(3- fluorobenzyl)tryptophan 81 N-{[4-(but-2- 46 and 47 5-chloroindole 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(4- chlorobenzyl)tryptophan 82 N-{[4-(but-2- 46 and 47 5-chloroindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1-(4- isopropylbenzyl)tryptophan 83 1-(1,3-benzodioxol-5- 46 and 47 5-chloroindole 5-bromomethyl- ylmethyl)-N-{[4-(but-2- benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-5- chlorotryptophan 84 N-{[4-(but-2- 46 and 47 5-chloroindole 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-5- pyridine chloro-1-(pyridin-3- ylmethyl)tryptophan 85 N-{[4-(but-2- 46 and 47 5-chloroindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide chloro-1- isobutyltryptophan 86 N-{[4-(but-2- 46 and 47 5-chloroindole bromomethyl- ynyloxy)phenyl]sulfonyl}-5- cyclobutane chloro-1- (cyclobutylmethyl)tryptophan 87 N-{[4-(but-2- 46 and 47 5-chloroindole bromomethyl- ynyloxy)phenyl]sulfonyl}-5- cyclohexane chloro-1- (cyclohexylmethyl)tryptophan 88 1-benzyl-N-{[4-(but-2- 46 and 47 5-chloro-2- benzyl bromide ynyloxy)phenyl]sulfonyl}-5- methylindole chloro-2-methyltryptophan 89 N-{[4-(but-2- 46 and 47 5-chloro-2- 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(2- methoxybenzyl)-2- methyltryptophan 90 N-{[4-(but-2- 46 and 47 5-chloro-2- 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(3- methoxybenzyl)-2- methyltryptophan 91 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(4- methoxybenzyl)-2- methyltryptophan 92 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-2-methyl-1-(4- methylbenzyl)tryptophan 93 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-2-methyl-1-[4- (trifluoromethyl)benzyl]tryptophan 94 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-trifluoromethoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-2-methyl-1-[4- (trifluoromethoxy)benzyl]tryptophan 95 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(4-fluorobenzyl)- 2-methyltryptophan 96 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(4-chlorobenzyl)- 2-methyltryptophan 97 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(4- isopropylbenzyl)-2- methyltryptophan 98 N-{[4-(but-2- 46 and 47 5-chloro-2- 4-cyanobenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-(4-cyanobenzyl)- 2-methyltryptophan 99 N-{[4-(but-2- 46 and 47 5-chloro-2- 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-5- methylindole pyridine chloro-2-methyl-1-(pyridin- 3-ylmethyl)tryptophan 100 1-(1,3-benzodioxol-5- 46 and 47 5-chloro-2- 5-bromomethyl- ylmethyl)-N-{[4-(but-2- methylindole benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-5- chloro-2-methyltryptophan 101 N-{[4-(but-2- 46 and 47 5-chloro-2- 2-methylpropyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide chloro-1-isobutyl-2- methyltryptophan 102 N-{[4-(but-2- 46 and 47 5-chloro-2- bromomethyl- ynyloxy)phenyl]sulfonyl}-5- methylindole cyclohexane chloro-1- (cyclohexylmethyl)-2- methyltryptophan 103 1-benzyl-N-{[4-(but-2- 46 and 47 1H-Indole-5- benzyl bromide ynyloxy)phenyl]sulfonyl}-5- carboxylic acid carboxytryptophan methyl ester 104 N-{[4-(but-2- 46 and 47 1H-Indole-5- 2-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(2- methyl ester methylbenzyl)tryptophan 105 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(3- methyl ester methylbenzyl)tryptophan 106 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(4- methyl ester methylbenzyl)tryptophan 107 N-{[4-(but-2- 46 and 47 1H-Indole-5- 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(2- methyl ester methoxybenzyl)tryptophan 108 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(3- methyl ester methoxybenzyl)tryptophan 109 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(4- methyl ester methoxybenzyl)tryptophan 110 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3,5-dimethoxybenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(3,5- methyl ester dimethoxybenzyl)tryptophan 111 N-{[4-(but-2- 46 and 47 1H-Indole-5- 2-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-[2- methyl ester (trifluoromethyl)benzyl]tryptophan 112 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-[3- methyl ester (trifluoromethyl)benzyl]tryptophan 113 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-[4- methyl ester (trifluoromethyl)benzyl]tryptophan 114 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-trifluoromethoxybenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-[4- methyl ester (trifluoromethoxy)benzyl]tryptophan 115 N-{[4-(but-2- 46 and 47 1H-Indole-5- 2-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(2- methyl ester fluorobenzyl)tryptophan 116 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(3- methyl ester fluorobenzyl)tryptophan 117 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(4- methyl ester fluorobenzyl)tryptophan 118 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3,5-difluorobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(3,5- methyl ester difluorobenzyl)tryptophan 119 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(4- methyl ester chlorobenzyl)tryptophan 120 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(4- methyl ester isopropylbenzyl)tryptophan 121 N-{[4-(but-2- 46 and 47 1H-Indole-5- 2-cyanobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(2- methyl ester cyanobenzyl)tryptophan 122 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3-cyanobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(3- methyl ester cyanobenzyl)tryptophan 123 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-cyanobenzyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1-(4- methyl ester cyanobenzyl)tryptophan 124 1-(1,3-benzodioxol-5- 46 and 47 1H-Indole-5- 5-bromomethyl- ylmethyl)-N-{[4-(but-2- carboxylic acid benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-5- methyl ester carboxytryptophan 125 N-{[4-(but-2- 46 and 47 1H-Indole-5- 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-5- carboxylic acid pyridine carboxy-1-(pyridin-3- methyl ester ylmethyl)tryptophan 126 N-{[4-(but-2- 46 and 47 1H-Indole-5- 4-Chloromethyl- ynyloxy)phenyl]sulfonyl}-5- carboxylic acid benzoic acid carboxy-1-(4- methyl ester carboxybenzyl)tryptophan 127 N-{[4-(but-2- 46 and 47 1H-Indole-5- iodomethane ynyloxy)phenyl]sulfonyl}-5- carboxylic acid carboxy-1- methyl ester methyltryptophan 128 N-{[4-(but-2- 46 and 47 1H-Indole-5- ethyl bromide ynyloxy)phenyl]sulfonyl}-5- carboxylic acid carboxy-1-ethyltryptophan methyl ester 129 N-{[4-(but-2- 46 and 47 1H-Indole-5- 2-methylpropyl ynyloxy)phenyl]sulfonyl}-5- carboxylic acid bromide carboxy-1- methyl ester isobutyltryptophan 130 N-{[4-(but-2- 46 and 47 1H-Indole-5- 1-bromo-pentane ynyloxy)phenyl]sulfonyl}-5- carboxylic acid carboxy-1- methyl ester pentyltryptophan 131 N-{[4-(but-2- 46 and 47 1H-Indole-5- bromomethyl- ynyloxy)phenyl]sulfonyl}-5- carboxylic acid cyclobutane carboxy-1- methyl ester (cyclobutylmethyl)tryptophan 132 N-{[4-(but-2- 46 and 47 1H-Indole-5- bromomethyl- ynyloxy)phenyl]sulfonyl}-5- carboxylic acid cyclohexane carboxy-1- methyl ester (cyclohexylmethyl)tryptophan 133 N-{[4-(but-2- 46 5-chloroindole N/A ynyloxy)phenyl]sulfonyl}-5- chlorotryptophan 134 N-{[4-(but-2- 46 2-methylindole N/A ynyloxy)phenyl]sulfonyl}-2- methyltryptophan 135 1-benzyl-N-{[4-(but-2- 46 and 47 5-cyanoindole benzyl bromide ynyloxy)phenyl]sulfonyl}-5- cyanotryptophan 136 N-{[4-(but-2- 46 and 47 5-cyanoindole 4-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide cyano-1-(4- methylbenzyl)tryptophan 137 N-{[4-(but-2- 46 and 47 5-cyanoindole 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide cyano-1-(2- methoxybenzyl)tryptophan 138 N-{[4-(but-2- 46 and 47 5-cyanoindole 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide cyano-1-(3- methoxybenzyl)tryptophan 139 N-{[4-(but-2- 46 and 47 5-cyanoindole 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- bromide cyano-1-(4- methoxybenzyl)tryptophan 140 N-{[4-(but-2- 46 and 47 5-cyanoindole 4- ynyloxy)phenyl]sulfonyl}-5- trifluoromethoxybenzyl cyano-1-[4- bromide (trifluoromethoxy)benzyl]tryptophan 141 N-{[4-(but-2- 46 and 47 5-cyanoindole 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-5- bromide cyano-1-(4- fluorobenzyl)tryptophan 142 N-{[4-(but-2- 46 and 47 5-cyanoindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide cyano-1-(4- isopropylbenzyl)tryptophan 143 N-{[4-(but-2- 46 and 47 5-cyanoindole 2- ynyloxy)phenyl]sulfonyl}-5- methylpropylbromide cyano-1- isobutyltryptophan 144 1-benzyl-N-{[4-(but-2- 46 and 47 2-methylindole benzyl bromide ynyloxy)phenyl]sulfonyl}-2- methyltryptophan 145 N-{[4-(but-2- 46 and 47 2-methylindole 2-methylbenzyl ynyloxy)phenyl]sulfonyl}-2- bromide methyl-1-(2- methylbenzyl)tryptophan 146 N-{[4-(but-2- 46 and 47 2-methylindole 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-methoxybenzyl)-2- methyltryptophan 147 N-{[4-(but-2- 46 and 47 2-methylindole 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-methoxybenzyl)-2- methyltryptophan 148 N-{[4-(but-2- 46 and 47 2-methylindole 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-methoxybenzyl)-2- methyltryptophan 149 N-{[4-(but-2- 46 and 47 2-methylindole 3- ynyloxy)phenyl]sulfonyl}-2- trifluoromethylbenzyl methyl-1-[3- bromide (trifluoromethyl)benzyl]tryptophan 150 N-{[4-(but-2- 46 and 47 2-methylindole 4- ynyloxy)phenyl]sulfonyl}-2- trifluoromethylbenzyl methyl-1-[4- bromide (trifluoromethyl)benzyl]tryptophan 151 N-{[4-(but-2- 46 and 47 2-methylindole 4- ynyloxy)phenyl]sulfonyl}-2- trifluoromethoxybenzyl methyl-1-[4- bromide (trifluoromethoxy)benzyl]tryptophan 152 N-{[4-(but-2- 46 and 47 2-methylindole 2-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-fluorobenzyl)-2- methyltryptophan 153 N-{[4-(but-2- 46 and 47 2-methylindole 3-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-fluorobenzyl)-2- methyltryptophan 154 N-{[4-(but-2- 46 and 47 2-methylindole 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-fluorobenzyl)-2- methyltryptophan 155 N-{[4-(but-2- 46 and 47 2-methylindole 3,5-difluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3,5-difluorobenzyl)-2- methyltryptophan 156 N-{[4-(but-2- 46 and 47 2-methylindole 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-chlorobenzyl)-2- methyltryptophan 157 N-{[4-(but-2- 46 and 47 2-methylindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-isopropylbenzyl)-2- methyltryptophan 158 N-{[4-(but-2- 46 and 47 2-methylindole 2-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-cyanobenzyl)-2- methyltryptophan 159 N-{[4-(but-2- 46 and 47 2-methylindole 3-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-cyanobenzyl)-2- methyltryptophan 160 N-{[4-(but-2- 46 and 47 2-methylindole 4-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-cyanobenzyl)-2- methyltryptophan 161 1-(1,3-benzodioxol-5- 46 and 47 2-methylindole 5-bromomethyl- ylmethyl)-N-{[4-(but-2- benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-2- methyltryptophan 162 N-{[4-(but-2- 46 and 47 2-methylindole 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-2- pyridine methyl-1-(pyridin-3- ylmethyl)tryptophan 163 N-{[4-(but-2- 46 and 47 2-methylindole ethyl bromide ynyloxy)phenyl]sulfonyl}-1- ethyl-2-methyltryptophan 164 N-{[4-(but-2- 46 and 47 2-methylindole 2-methylpropylbromide ynyloxy)phenyl]sulfonyl}-1- isobutyl-2- methyltryptophan 165 N-{[4-(but-2- 46 and 47 2-methylindole bromomethyl- ynyloxy)phenyl]sulfonyl}-1- cyclobutane (cyclobutylmethyl)-2- methyltryptophan 166 N-{[4-(but-2- 46 and 47 2-methylindole bromomethyl- ynyloxy)phenyl]sulfonyl}-1- cyclohexane (cyclohexylmethyl)-2- methyltryptophan 167 1-benzyl-N-{[4-(but-2- 46 and 47 5-methylindole benzyl bromide ynyloxy)phenyl]sulfonyl}-5- methyltryptophan 168 N-{[4-(but-2- 46 and 47 5-methylindole 2-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methyl-1-(2- methylbenzyl)tryptophan 169 N-{[4-(but-2- 46 and 47 5-methylindole 3-metrhylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methyl-1-(3- methylbenzyl)tryptophan 170 N-{[4-(but-2- 46 and 47 5-methylindole 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (2-methoxybenzyl)-5- methyltryptophan 171 N-{[4-(but-2- 46 and 47 5-methylindole 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-methoxybenzyl)-5- methyltryptophan 172 N-{[4-(but-2- 46 and 47 5-methylindole 2-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methyl-1-[2- (trifluoromethyl)benzyl]tryptophan 173 N-{[4-(but-2- 46 and 47 5-methylindole 3-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methyl-1-[3- (trifluoromethyl)benzyl]tryptophan 174 N-{[4-(but-2- 46 and 47 5-methylindole 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- bromide methyl-1-[4- (trifluoromethyl)benzyl]tryptophan 175 N-{[4-(but-2- 46 and 47 5-methylindole 3-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3-fluorobenzyl)-5- methyltryptophan 176 N-{[4-(but-2- 46 and 47 5-methylindole 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-fluorobenzyl)-5- methyltryptophan 177 N-{[4-(but-2- 46 and 47 5-methylindole 3,5-difluorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (3,5-difluorobenzyl)-5- methyltryptophan 178 N-{[4-(but-2- 46 and 47 5-methylindole 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-chlorobenzyl)-5- methyltryptophan 179 N-{[4-(but-2- 46 and 47 5-methylindole 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-isopropylbenzyl)-5- methyltryptophan 180 1-(1,3-benzodioxol-5- 46 and 47 5-methylindole 5-bromomethyl- ylmethyl)-N-{[4-(but-2- benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-5- methyltryptophan 181 N-{[4-(but-2- 46 and 47 5-methylindole 3-bromomethyl- ynyloxy)phenyl]sulfonyl}-5- pyridine methyl-1-(pyridin-3- ylmethyl)tryptophan 182 N-{[4-(but-2- 46 and 47 5-methylindole ethyl bromide ynyloxy)phenyl]sulfonyl}-1- ethyl-5-methyltryptophan 183 N-{[4-(but-2- 46 and 47 5-methylindole 2-methylpropylbromide ynyloxy)phenyl]sulfonyl}-1- isobutyl-5- methyltryptophan 184 N-{[4-(but-2- 46 and 47 5-methylindole 1-bromo-pentane ynyloxy)phenyl]sulfonyl}-5- methyl-1-pentyltryptophan 185 1-benzyl-N-{[4-(but-2- 46 and 47 5-methoxy-2- benzyl bromide ynyloxy)phenyl]sulfonyl}-5- methylindole methoxy-2- methyltryptophan 186 N-{[4-(but-2- 46 and 47 5-methoxy-2- 2-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-(2- methylbenzyl)tryptophan 187 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-(3- methylbenzyl)tryptophan 188 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-methylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-(4- methylbenzyl)tryptophan 189 N-{[4-(but-2- 46 and 47 5-methoxy-2- 2-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-1-(2- methoxybenzyl)-2- methyltryptophan 190 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-1-(3- methoxybenzyl)-2- methyltryptophan 191 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-methoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-1-(4- methoxybenzyl)-2- methyltryptophan 192 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3,5-dimethoxybenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (3,5-dimethoxybenzyl)-5- methoxy-2- methyltryptophan 193 N-{[4-(but-2- 46 and 47 5-methoxy-2- 2-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-[2- (trifluoromethyl)benzyl]tryptophan 194 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3-trifluoromethoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-[3- (trifluoromethoxy)benzyl]tryptophan 195 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-trifluoromethylbenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-[4- (trifluoromethyl)benzyl]tryptophan 196 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-trifluoromethoxybenzyl ynyloxy)phenyl]sulfonyl}-5- methylindole bromide methoxy-2-methyl-1-[4- (trifluoromethoxy)benzyl]tryptophan 197 N-{[4-(but-2- 46 and 47 5-methoxy-2- 2-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (2-fluorobenzyl)-5- methoxy-2- methyltryptophan 198 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (3-fluorobenzyl)-5- methoxy-2- methyltryptophan 199 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-fluorobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (4-fluorobenzyl)-5- methoxy-2- methyltryptophan 200 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3,5-difluorobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (3,5-difluorobenzyl)-5- methoxy-2- methyltryptophan 201 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-chlorobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (4-chlorobenzyl)-5- methoxy-2- methyltryptophan 202 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-isopropylbenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (4-isopropylbenzyl)-5- methoxy-2- methyltryptophan 203 N-{[4-(but-2- 46 and 47 5-methoxy-2- 2-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (2-cyanobenzyl)-5- methoxy-2- methyltryptophan 204 N-{[4-(but-2- 46 and 47 5-methoxy-2- 3-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (3-cyanobenzyl)-5- methoxy-2- methyltryptophan 205 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-cyanobenzyl ynyloxy)phenyl]sulfonyl}-1- methylindole bromide (4-cyanobenzyl)-5- methoxy-2- methyltryptophan 206 1-(1,3-benzodioxol-5- 46 and 47 5-methoxy-2- 5-bromomethyl- ylmethyl)-N-{[4-(but-2- methylindole benzo[1,3]dioxole ynyloxy)phenyl]sulfonyl}-5- methoxy-2- methyltryptophan 207 N-{[4-(but-2- 46 and 47 5-methoxy-2- 4-bromomethyl- ynyloxy)phenyl]sulfonyl}-1- methylindole benzoic acid (4-carboxybenzyl)-5- methoxy-2- methyltryptophan 208 N-{[4-(but-2- 46 and 47 5-methoxy-2- iodomethane ynyloxy)phenyl]sulfonyl}-5- methylindole methoxy-1,2- dimethyltryptophan 209 N-{[4-(but-2- 46 and 47 5-methoxy-2- iodoethane ynyloxy)phenyl]sulfonyl}-1- methylindole ethyl-5-methoxy-2- methyltryptophan 210 N-{[4-(but-2- 46 and 47 5-methoxy-2- 2-methylpropylbromide ynyloxy)phenyl]sulfonyl}-1- methylindole isobutyl-5-methoxy-2- methyltryptophan 211 N-{[4-(but-2- 46 and 47 5-methoxy-2- 1-bromo-pentane ynyloxy)phenyl]sulfonyl}-5- methylindole methoxy-2-methyl-1- pentyltryptophan 212 N-{[4-(but-2- 46 and 47 5-methoxy-2- bromomethyl- ynyloxy)phenyl]sulfonyl}-1- methylindole cyclobutane (cyclobutylmethyl)-5- methoxy-2- methyltryptophan 213 N-{[4-(but-2- 46 and 47 5-methoxy-2- bromomethyl- ynyloxy)phenyl]sulfonyl}-1- methylindole cyclohexane (cyclohexylmethyl)-5- methoxy-2- methyltryptophan 214 N-{[4-(but-2- 6 (step 1) and 7 indole p-hydroxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-hydroxybenzyl)-D- tryptophan 215 N-{[4-(but-2- 6 (step 1) and 7 indole p-ethoxybenzyl ynyloxy)phenyl]sulfonyl}-1- bromide (4-ethoxybenzyl)-D- tryptophan 216 1-[4-(allyloxy)benzyl]-N- 6 (step 1) and 7 indole p-allylbenzyl {[4-(but-2- bromide ynyloxy)phenyl]sulfonyl}- D-tryptophan 217 N-{[4-(but-2- 6 (step2) 5-methyltryptophan N/A ynyloxy)phenyl]sulfonyl}-5- meth-D(or L)-tryptophan 218 N-{[4-(but-2- 6 (step2) 5-methyltryptophan N/A ynyloxy)phenyl]sulfonyl}-5- methyl(or D)-L-tryptophan 219 1-(tert-butoxycarbonyl)-N- 6 (step 1) 1-tert-butoxy N/A {[4-(but-2- carbonyl-L- ynyloxy)phenyl]sulfonyl}-L- tryptophan tryptophan 220 1-(tert-butoxycarbonyl)-N- 6 (step 1) 1-tert-butoxy N/A {[4-(but-2- carbonyl-D- ynyloxy)phenyl]sulfonyl}- tryptophan D-tryptophan 221 N-{[4-(but-2- 4 (step2) 5-methoxytryptophan N/A ynyloxy)phenyl]sulfonyl}-5- methoxy-D(or L)- tryptophan 222 N-{[4-(but-2- 4 (step2) 5-methoxytryptophan N/A ynyloxy)phenyl]sulfonyl}- methoxy-L(or D)- tryptophan 223 5-(benzyloxy)-N-{[4-(but-2- 20 (step 2) 5-benzyloxytryptophan N/A ynyloxy)phenyl]sulfonyl}- D(or L)-tryptophan 224 5-(benzyloxy)-N-{[4-(but-2- 20 (step 2) 5-benzyloxytryptophan N/A ynyloxy)phenyl]sulfonyl}- L(or D)-tryptophan Determination of Activity

Standard pharmacological test procedures are readily available to determine the ability of compounds of the invention to inhibit TACE. Generally, TACE inhibition is determined by the ability to inhibit TACE mediated cleavage of a TNF-α precursor (pro-TNF protein), or a TACE substrate (such as pro-TNF peptide) that contains the same scissile amide bond as that of the TNF-α precursor. The inhibition is generally reported as the percentage of inhibition of the cleavage of the TNF-α precursor (or a TACE substrate), or as the IC₅₀ (the concentration required for 50% inhibition). Some exemplary standard pharmacological test procedures for TACE inhibition are provided in (a) Jin, G., et al. (2002) Analytical Biochemistry 302: 269-275; (b) Newton, R C, et al. (2001) Ann Rheum Dis. 60: iii25-iii32; and (c) Knight, C. G., et al. FEBS Lett. (1992) 296: 263-266, each of which is hereby incorporated by reference in its entirety.

Biological Assays of Compounds of the Invention

TACE FRET Assay Using TACE Cat

The procedure is essentially as described in Jin, G. et al., Analytical Biochemistry (2002) 302: 269-275, incorporated by reference herein in its entirety. The basic measurement of the assay is the percentage of inhibition of the cleavage of the fluorogenic pro-TNF peptide by TACE or the IC₅₀ determination by a fitting with the model-39 of LSW data analysis tool, which processes data according to the equation y=((B*Kˆn)+(100*xˆn))/(Kˆn+xˆn), a sigmoidal curve with Hill slope, B to 100. “K” is the IC₅₀. Generally, “n” and “B” are floated, noting that n (Hill slope) should be close to 1 and B (background offset) to 0.

Pro-TNF-α substrate peptide Abz-LAQAVRSSSR-Dpa (AnaSpec, San Jose, Calif., WARC-1) was prepared as a 2 mM stock solution in the TACE assay buffer (50 mM Tris-HCl, pH 7.4, 25 mM NaCl, 4% Glycerol, 0.005% Brij 35). The catalytic domain of the recombinant TACE protein was expressed and purified. The TACE protein (1 ug/ml) was pretreated with the inhibitors at various concentrations for 10 min. at room temperature. The reaction was initiated by the addition of the substrate peptide. The increase in fluorescence was monitored at an Excitation of 320 nM and an Emission of 420 nM over a period of 10 min. The initial rate (slope) of the reaction was determined using a fluorescence plate reader (Molecular Devices, Spectra Max Gemini XS).

Compounds with IC₅₀ or % inhibition at 1 μM in TACE FRET assay are shown in the following Table 1. TABLE 1 TACE FRET assay TACE Conc. Inhibition TACE IC₅₀ Example (μM) (%) (μM) 35 0.08 218 0.14 221 0.14 91 0.19 185 0.20 190 0.26 188 0.27 186 0.28 6 0.28 201 0.29 197 0.30 199 0.32 198 0.34 4 0.36 206 0.36 224 0.37 193 0.45 205 0.47 204 0.48 216 0.54 20 0.75 27 0.97 36 0.98 19 1.19 69 1.19 67 1.23 24 1.25 68 1.32 21 1.40 65 1.50 3 1.56 8 1.57 5 1.61 23 1.71 70 1.87 28 1.90 56 2.07 25 2.15 58 2.24 52 2.24 40 2.30 22 2.31 1 2.53 7 2.96 42 3.45 26 3.59 220 3.67 45 4.04 41 4.40 223 6.98 2 8.20 222 10.11 194 1 80.79 200 1 80.51 192 1 79.96 187 1 78.82 195 1 78.26 191 1 77.47 189 1 75.58 133 1 73.86 196 1 72.82 211 1 72.24 158 1 72.13 209 1 69.80 215 1 69.46 101 1 68.50 202 1 66.99 210 1 66.62 90 1 65.20 134 1 64.21 92 1 63.95 95 1 63.58 88 1 62.83 207 1 62.08 208 1 61.79 98 1 60.95 213 1 60.49 212 1 59.50 136 1 57.82 102 1 56.94 203 1 56.75 96 1 56.49 153 1 55.87 100 1 55.64 155 1 54.33 93 1 53.77 89 1 53.59 154 1 52.70 152 1 51.70 149 1 50.47 145 1 49.53 94 1 47.36 59 1 44.39 148 1 44.08 60 1 43.49 156 1 43.30 64 1 40.87 61 1 39.52 62 1 39.33 49 1 38.85 51 1 38.28 54 1 37.95 87 1 37.44 48 1 37.24 146 1 35.89 150 1 35.64 147 1 35.59 157 1 34.24 85 1 32.94 143 1 32.39 57 1 32.13 55 1 31.34 83 1 31.07 50 1 30.59 53 1 30.58 77 1 29.75 135 1 29.60 141 1 29.59 138 1 29.41 63 1 28.18 73 1 28.03 72 1 27.48 80 1 27.12 139 1 25.08 75 1 24.97 151 1 24.34 97 1 21.90 144 1 18.84 76 1 18.32 140 1 15.98 86 1 15.71 74 1 15.04 121 1 14.75 81 1 13.92 137 1 12.10 119 1 11.73 105 1 11.00 117 1 10.89 111 1 10.74 114 1 10.35 124 1 10.17 120 1 10.02 108 1 9.93 116 1 9.72 132 1 9.55 214 1 8.77 126 1 8.36 142 1 8.34 79 1 8.27 110 1 8.02 109 1 7.93 78 1 7.39 107 1 7.34 125 1 6.23 103 1 6.16 118 1 5.98 104 1 5.79 106 1 5.53 112 1 5.51 82 1 5.26 115 1 4.29 122 1 −0.34 128 1 −0.60 71 1 −1.19 131 1 −1.21 113 1 −2.04 123 1 −2.56 127 1 −3.22 129 1 −4.96 130 1 −5.71

Human Whole Blood Assay for LPS-Induced TNF-a Secretion

The procedure is essentially as described in Newton, R. C., et al., (2001) Ann Rheum Dis. 60, iii25-iii32, incorporated by reference herein in its entirety. The basic measurement of the assay is the percentage of inhibition of TNF-α secretion and the IC₅₀ determination by a fitting with the model-39 of LSW data analysis tool.

Three hundred fifty microliters (350 μl) of fresh human blood drawn from healthy volunteers were pre-incubated with compounds for one hour at the various concentrations at 37° C. with turning. Generally, the final DMSO concentrations should be kept below 0,2%. At the end of the incubation, LPS (Sigma, L2262) was added to the blood at 100 ng/ml and the samples were further incubated for 4 hours or overnight at 37 ° C. with constant rotation. At the end of the incubation period, 650 μl of serum-free medium was added to the blood samples and the samples were centrifuged at 1500 rpm for 15 minutes. Five hundred microliters (500 μl) of supernate were collected and frozen at −80° C.

The TNF-α and other proinflammatory cytokines were detected by ELISA assay according to the manufacturer's instruction (Biosource International, Inc., Camarillo, Calif.). Table 2 shows the results for a compound of the invention. TABLE 2 TNF-α Secretion in Human Whole Blood Example IC₅₀ (μM) 218 >50

Cell-Based Assay for Inhibition of TNF-a Secretion in Raw Cells

The basic measurement of the assay is the percentage of inhibition of TNF-α secretion and the IC₅₀ determination by a fitting with the model-39 of LSW data analysis tool.

Raw 264.7 cells (ATCC Cat No. TIB-71) are maintained in DMEM medium containing 10% of serum, P/S, and Glutamine. Cells are split twice a week by scraping and 1 to 10 or 20 dilutions. For testing compounds, cells are cultured to confluence and are seeded the day before the experiment in 24 well culture dishes at 0.5 to 1 million/ml/well. On the next morning, the medium from the overnight culture is replaced with the fresh growth medium. The compounds are added at various concentrations at the 0.2% of final DMSO concentrations (10 μl of a 20% DMSO solution containing testing compounds is added to each well). The cells are pre-incubated with compounds for 1 hour. LPS (Sigma, L2262) is added to cells at a final concentration of 100 ng/ml (10 μl of a 10 μM LPS solution freshly diluted from a 1 mg/ml LPS stock solution in PBS is added to each well) and cells are further incubated for 4 hours at 37° C. One milliliter (1 ml) of the supernatant was collected, cells are spun down and the supernatants are frozen at −80° C. until use.

The TNF-α and other proinflammatory cytokines were detected by ELISA assay according to the manufacturer's instruction (Biosource International, Inc., Camarillo, Calif.) (For IL-1b measurement in Raw cells, one round of freeze and thaw of the cells was required.)

Results for representative compounds of the invention are shown in Table 3. TABLE 3 TNF-α Secretion in Raw Cells Conc. Lo Conc. Hi IC₅₀ Example (μM) (μM) (μM) 24 >60 27 >60 35 >60 199 0.016 40 >60 218 7.11 221 57

In-Vitro Fluorescence Assay of MMP-1 Activity

A continuous assay was used in which the substrate is a synthetic peptide containing a fluorescent group (7-methoxycoumarin; Mca) that is quenched by energy transfer to a 2,4-dinitrophenyl group. See Knight, C. G. et al., FEBS Lett. (1992) 296: 263-266, incorporated herein by reference in its entirety. When the peptide was cleaved by MMP, a large increase in fluorescence was observed. The source of enzyme in the assay was the recombinant human catalytic domain of MMP-1. See Zhang, Y et al., Journal of Pharmacology and Experimental Therapeutics (JPET) (2004) 309:348-355, incorporated by reference in its entirety. The substrate used was Mca-PQGL-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-AR-OH (denoted as Wammp-5, custom synthesized by AnaSpec, Inc., San Jose, Calif.). The assay buffer consisted of 50 mM Hepes (pH 7.4), 100 mM NaCl, 5 mM CaCl₂, and 0.005% Brij-35. Each well of black polystyrene 96-well plates contained a 200 μl reaction mixture consisting of assay buffer, purified MMP (final concentration of 25 ng/ml, prepared by diluting with the assay buffer), and varied concentrations of inhibitor (prepared by serially diluting a given inhibitor in DMSO in 96-well polypropylene plate). The plates were then incubated at 30° C. for 15 minutes. The enzymatic reactions were initiated by adding the substrate to a final concentration of 20 μM, and mixing 10 times with a pipette. The final DMSO concentration in the assay was 6.0%. The initial rate of the cleavage reaction was determined at 30° C. with a fluorescence plate reader (excitation filter of 330 nm and emission filter of 395 nm) immediately after substrate addition.

Plots of the inhibitor concentration versus the percent inhibition were fit to the following equation: y=(a−d)/[1+(x/c)^(b)]+d, a general sigmoidal curve with Hill slope, a to d. x is the inhibitor concentration under test. “y” is the percent inhibition. “a” is the limiting response as x approaches zero. As x increases without bound, y tends toward its limit d. “c” is the inflection point (IC₅₀) for the curve. That is, y is halfway between the lower and upper asymptotes when x=c. “b” is the slope factor or Hill coefficient.

Results for representative compounds of the invention are shown in Table 4. TABLE 4 MMP-1 FRET Assay Conc. MMP-1 Inhibition Example (μM) (%) 218 160 30 4 1000 33 35 33 14 47 67 30 221 83 9 224 83 19

In-Vitro Fluorescence Assay of MMP-13 Activity

The procedure is essentially the same as for the in-vitro fluorescence assay of MMP-1 activity, except that the source of enzyme in the assay was the recombinant human catalytic domain of MMP-13 (165 amino acids, residues 104-268, 19 kDa). See Zhang, Y et al., Journal of Pharmacology and Experimental Therapeutics (JPET) (2004) 309:348-355, incorporated by reference in its entirety.

Results for representative compounds of the invention are shown in Table 5. TABLE 5 MMP-13 FRET Assay MMP-13 MMP-13 Conc. Inhibition IC₅₀ Example (μM) (%) (μM) 4 15 50 6 6.87 20 15.3 28 17 35 4.56 218 1.81 47 3 50 221 13.6 224 4.44

In-Vitro Fluorescence Assay of MMP-14 Activity

The procedure is essentially the same as for the in-vitro fluorescence assay of MMP-1 activity, except that the source of enzyme in the assay was the recombinant human catalytic domain of MMP-14 (177 amino acids corresponding to Tyr89-Gly265 of mature human enzyme; 20 kDa) purchased from Chemicon International, Inc. (Temecula, Calif.; catalog number CC1041).

Results for representative compounds of the invention are shown in Table 6. TABLE 6 MMP-14 FRET Assay MMP-14 IC₅₀ Example (μM) 218 6.82 4 22.7 35 13 47 11.6 221 20.7 224 19.7

In-Vitro Fluorescence Assay of MMP-2 Activity

The procedure is essentially the same as for the in-vitro fluorescence assay of MMP-1 activity, except that the source of enzyme in the assay was the recombinant human MMP-2 (66 kDa) purchased from Oncogene Research Products (catalog number PF023 from Calbiochem, San Diego, Calif.).

Results for representative compounds of the invention are shown in Table 7. TABLE 7 MMP-2 FRET Assay MMP-2 IC₅₀ Example (μM) 4 7.84 6 1.16 20 7.85 28 3.97 35 1.44 218 0.27 47 0.66 221 1.27 224 2.45

It is intended that each of the patents, applications, and printed publications, including books, mentioned herein be hereby incorporated by reference in their entirety.

As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the scope of the invention. 

1. A compound having the Formula I:

wherein: R₁ is H, aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, or C₄₋₈-cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR₅, S and O; wherein each of said aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl or aralkyl can be optionally substituted with up to four independently selected R₁₄ groups; R₂, R₃ and R₄ are each, independently, H, C₁₋₈ alkyl, halogen, CN, CCH, OH, or OR₁; R₅, R₆, R₇, R₈, R₉ and R₁₀ are each, independently, H, aryl, heteroaryl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aralkyl, heteroalkyl, heteroarylalkyl, halogen, CN, hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, NR₁₁R₁₁, COOR₁₁, OR₁₁, or C₄₋₈ cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR₁₁, S and O; wherein each of said aryl, heteroaryl, heteroalkyl, heteroarylalkyl, C₄₋₈ cycloheteroalkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, or aralkyl can be optionally substituted with up to four independently selected R₁₅ groups; wherein one or more than one of the pairs R₄ and R₆, R₄ and R₇, R₅ and R₆, R₅ and R₁₀, R₇ and R₈, R₈ and R₉ or R₉ and R₁₀, together with the carbon atom or atoms to which they attached, can form a cycloalkyl ring having 3-8 carbon atoms, or a C₄₋₈ cycloheteroalkyl ring; R₁₁ is H, aryl, heteroaryl, aralkyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, oxy, halogen, hydroxyalkyl, alkoxy, alkoxy-alkyl, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, C₁₋₈ alkanoyl, COOR₁, COR₁, SO₂—C₁₋₈ alkyl, SO₂-aryl, SO₂-heteroaryl, or CO—NHR₁; wherein each of said aryl, heteroaryl, aralkyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, SO₂—C₁₋₈ alkyl, SO₂-aryl and SO₂-heteroaryl can be optionally substituted with up to four independently selected R₁₆ groups; each R₁₄, R₁₅ and R₁₆ is, independently, halogen, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, —OR₁₇, CN, COR₁₂, C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ perhaloalkoxy, C₁₋₆ perfluoroalkyl, —O—C₁₋₆ perfluoroalkyl, CONR₁₂R₁₃, —OPO(OR_(12a))OR_(13a), —PO(OR_(12a))R₁₃, —OC(O)OR_(12a), —O—C₁₋₁₆ alkyl-NR₁₂R₁₃, —OC(O)NR₁₂R₁₃, —C(O)NR₁₂OR_(13a), —COOR_(12a), —SO₃H, —NR₁₂R₁₃, —N(R₂₀)(C₁₋₆ alkyl)NR₁₂, —N(R₂₀)COR₁₃, —N(R₂₀)COOR_(13a), —SO₂NR₁₂R₁₃, NO₂, —N(R₂₀)SO₂R₁₃, —N(R₂₀)CONR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)NR₁₂R₁₃, —N(R₂₀)C(═NR₁₃)N(SO₂R₁₂)R₁₃, —N(R₂₀)C(═NR₁₃)N(C═OR₁₂)R₁₃, -tetrazol-5-yl, —SO₂NHCN, —SO₂NHCONR₁₂R₁₃, aryl, phenyl, heteroaryl, —C₅₋₈ cycloheteroalkyl, CH₂—OR₂₂, —SR₂₂, —CH₂—SR₂₂, —SO₂NR₁₂R₁₃, —C(═NR₂₂)—, —C(NCN)R₂₂—, —CSN(R₂₂)₂, —C(NH)N(R₂₂)₂, NO₂, NO₃, azido, hydrazino, hydroxylamino, disulfide, urea, guanidine, or —S(O)_(n)R₁₂ wherein n is 0, 1 or 2; or any two R₁₄, R₁₅ or R₁₆ groups, when attached to an aryl, aralkyl, heteroaryl or heteroarylalkyl group, can together form a group of formula —O—(CH₂)_(k)—O— wherein k is 1 or 2; each R₁₂ and R₁₃ is, independently, H, OH, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, perfluoroalkoxy, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl; or —NR₁₂R₁₃ may form a pyrrolidine, piperidine, morpholine, thiomorphohne, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring; each R_(12a) and R_(13a) is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₃ perfluoroalkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl, or C₄₋₈ cycloheteroalkyl; each R₂₀ is, independently, H or C₁₋₆ alkyl; each R₁₇ is, independently, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, alkoxy-alkyl, aralkyl or C₄₋₈ cycloheteroalkyl; R₂₁ is H or C₁₋₈ alkyl; each R₂₂ is, independently, H or C₁₋₃ alkyl; A is SO₂ or —P(O)—R₁₀; X is O, NH, CH₂ or S; and Y is aryl or heteroaryl; with the proviso that A and X are not bonded to adjacent atoms of Y; or a pharmaceutically acceptable salt or prodrug thereof.
 2. A compound of claim 1 wherein A is SO₂.
 3. A compound of claim 1 wherein X is
 0. 4. A compound of claim 1 wherein Y is aryl.
 5. A compound of claim 1 wherein Y is phenyl.
 6. A compound of claim 1 wherein Y is heteroaryl.
 7. A compound of claim 1 wherein Y is pyridyl, thienyl, furanyl, imidazolyl, triazolyl or thiadiazolyl.
 8. A compound of claim 1 wherein R₁ is H or C₁₋₆ alkyl.
 9. A compound of claim 1 wherein R₂ and R₃ are each H.
 10. A compound of claim 1 wherein R₇ is H.
 11. A compound of claim 1 wherein R₂, R₃ and R₇ are each H.
 12. A compound of claim 1 wherein R₁ is H or C₁₋₆ alkyl; R₂, R₃ and R₇ are each H; A is SO₂; X is 0; and Y aryl.
 13. A compound of claim 12 wherein Y is phenyl.
 14. A compound of claim 1 having the Formula II:

or a pharmaceutically acceptable salt thereof or prodrug thereof.
 15. A compound of claim 14 wherein: R₅ is H, C₁₋₆ alkyl, C₂₋₈ alkenyl, arylalkyl, cycloalkylalkyl, CO₂R₁₁, aryloxyalkyl or heteroarylalkyl, wherein said arylalkyl is optionally substituted with up to four substituents independently selected from the group consisting of C₁₋₆ alkyl, halogen, C₁₋₈ alkoxy, aryl, phenyl, C₁₋₃ haloalkyl, C₁₋₃ perhaloalkyl, C₁₋₃ haloalkoxy, C₁₋₃ perhaloalkoxy, CN, alkenyloxy, CO₂H and OH, wherein any two adjacent hydroxyl groups attached to the aryl moiety of said arylalkyl can be joined together to form a 1,3-dioxolane group; R₆ is H or C₁₋₆ alkyl; R₈ is H, C₁₋₆ alkyl, C₁₋₆ alkoxy, OH, arylalkoxy, halogen, CO₂H or CN; R₉ is H, halogen or C₁₋₆ alkyl; R₁₀ is H or C₁₋₆ alkyl; and R₁₁ is C₁₋₆ alkyl; or a pharmaceutically acceptable salt thereof or prodrug thereof.
 16. A compound of claim 15 wherein R₄ is H.
 17. A compound of claim 15 wherein R₅ is H or arylalkyl, wherein said arylalkyl is optionally substituted with up to three C₁₋₃ alkoxy groups.
 18. A compound of claim 15 wherein R₆ is H or methyl.
 19. A compound of claim 15 wherein R₈ is H, halogen, C₁₋₃ alkyl, or C₁₋₃ alkoxy.
 20. A compound of claim 15 wherein R₉ is H.
 21. A compound of claim 15 wherein R₁₀ is H.
 22. A compound of claim 15 wherein R₉ and R₁₀ are each H.
 23. A compound of claim 15 wherein R₄, R₉ and R₁₀ are each H.
 24. A compound of claim 15 wherein R₄, R₉ and R₁₀ are each H; R₅ is H or arylalkyl, wherein said arylalkyl is optionally substituted with up to three C₁₋₃ alkoxy groups; R₆ is H or methyl; and R₈ is H, halogen, C₁₋₃ alkyl, or C₁₋₃ alkoxy.
 25. A compound of claim 15 wherein R₄, R₉ and R₁₀ are each H; R₅ is H or benzyl, wherein said benzyl is optionally substituted with up to three methoxy groups; R₆ is H or methyl; and R₈ is H, halogen, methyl or methoxy.
 26. A compound of claim 1 that is selected from compounds 1-224 below:
 1. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-D-tryptophan
 2. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-L-tryptophan
 3. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-fluorotryptophan
 4. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxytryptophan
 5. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-hydroxytryptophan
 6. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyltryptophan
 7. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-6-fluorotryptophan
 8. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-6-methyltryptophan
 9. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-alpha-methyltryptophan
 10. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-7-methyltryptophan
 11. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-hydroxy-L-tryptophan
 12. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-propyl-L-tryptophan
 13. 1-butyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-L-tryptophan
 14. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-isobutyl-L-tryptophan
 15. 1-allyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-L-tryptophan
 16. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-methylbenzyl)-L-tryptophan
 17. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methylbenzyl)-L-tryptophan
 18. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-L-tryptophan
 19. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methoxybenzyl)-L-tryptophan
 20. 5-(benzyloxy)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}tryptophan
 21. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-methyl-D-tryptophan
 22. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-pentyl-D-tryptophan
 23. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclohexylmethyl)-D-tryptophan
 24. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-phenoxybutyl)-D-tryptophan
 25. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-D-tryptophan
 26. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methylbenzyl)-D-tryptophan
 27. 1-(11′-biphenyl-2-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-D-tryptophan
 28. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-fluorobenzyl)-D-tryptophan
 29. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-naphthylmethyl)-D-tryptophan
 30. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(pyridin-3-ylmethyl)-D-tryptophan
 31. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclopropylmethyl)-D-tryptophan
 32. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclobutylmethyl)-D-tryptophan
 33. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-cyclohexylethyl)-D-tryptophan
 34. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-methoxybenzyl)-D-tryptophan
 35. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methoxybenzyl)-D-tryptophan
 36. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-dimethoxybenzyl)-D-tryptophan
 37. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-D-tryptophan
 38. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-[4-(trifluoromethoxy)benzyl]-D-tryptophan
 39. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-[2-(trifluoromethyl)benzyl]-D-tryptophan
 40. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-[3-(trifluoromethyl)benzyl]-D-tryptophan
 41. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-[4-(trifluoromethyl)benzyl]-D-tryptophan
 42. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-D-tryptophan
 43. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-cyanobenzyl)-D-tryptophan
 44. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-cyanobenzyl)-D-tryptophan
 45. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-cyanobenzyl)-D-tryptophan
 46. 5-bromo-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}tryptophan
 47. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methoxybenzyl)-5-methyltryptophan
 48. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxytryptophan
 49. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(2-methylbenzyl)tryptophan
 50. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(3-methylbenzyl)tryptophan
 51. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(2-methoxybenzyl)tryptophan
 52. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(3-methoxybenzyl)tryptophan
 53. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(4-methoxybenzyl)tryptophan
 54. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-dimethoxybenzyl)-5-methoxytryptophan
 55. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-[2-(trifluoromethyl)benzyl]tryptophan
 56. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-[3-(trifluoromethyl)benzyl]tryptophan
 57. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-[4-(trifluoromethyl)benzyl]tryptophan
 58. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-fluorobenzyl)-5-methoxytryptophan
 59. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-fluorobenzyl)-5-methoxytryptophan
 60. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-fluorobenzyl)-5-methoxytryptophan
 61. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-difluorobenzyl)-5-methoxytryptophan
 62. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-5-methoxytryptophan
 63. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-isopropylbenzyl)-5-methoxytryptophan
 64. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-cyanobenzyl)-5-methoxytryptophan
 65. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxytryptophan
 66. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(pyridin-3-ylmethyl)tryptophan
 67. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-isobutyl-5-methoxytryptophan
 68. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-pentyltryptophan
 69. N-{([4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclobutylmethyl)-5-methoxytryptophan
 70. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclohexylmethyl)-5-methoxytryptophan
 71. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chlorotryptophan
 72. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(2-methylbenzyl)tryptophan
 73. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(3-methylbenzyl)tryptophan
 74. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(2-methoxybenzyl)tryptophan
 75. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(3-methoxybenzyl)tryptophan
 76. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-methoxybenzyl)tryptophan
 77. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-[4-(trifluoromethyl)benzyl]tryptophan
 78. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-[4-(trifluoromethoxy)benzyl]tryptophan
 79. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(2-fluorobenzyl)tryptophan
 80. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(3-fluorobenzyl)tryptophan
 81. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-chlorobenzyl)tryptophan
 82. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-isopropylbenzyl)tryptophan
 83. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chlorotryptophan
 84. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(pyridin-3-ylmethyl)tryptophan
 85. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-isobutyltryptophan
 86. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(cyclobutylmethyl)tryptophan
 87. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(cyclohexylmethyl)tryptophan
 88. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-2-methyltryptophan
 89. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(2-methoxybenzyl)-2-methyltryptophan
 90. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(3-methoxybenzyl)-2-methyltryptophan
 91. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-methoxybenzyl)-2-methyltryptophan
 92. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-2-methyl-1-(4-methylbenzyl)tryptophan
 93. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-2-methyl-1-[4-(trifluoromethyl)benzyl]tryptophan
 94. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-2-methyl-1-[4-(trifluoromethoxy)benzyl]tryptophan
 95. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-fluorobenzyl)-2-methyltryptophan
 96. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-chlorobenzyl)-2-methyltryptophan
 97. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-isopropylbenzyl)-2-methyltryptophan
 98. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-cyanobenzyl)-2-methyltryptophan
 99. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-2-methyl-1-(pyridin-3-ylmethyl)tryptophan
 100. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-2-methyltryptophan
 101. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-isobutyl-2-methyltryptophan
 102. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(cyclohexylmethyl)-2-methyltryptophan
 103. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxytryptophan
 104. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(2-methylbenzyl)tryptophan 105 N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(3-methylbenzyl)tryptophan
 106. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-methylbenzyl)tryptophan
 107. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(2-methoxybenzyl)tryptophan
 108. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(3-methoxybenzyl)tryptophan
 109. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-methoxybenzyl)tryptophan
 110. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(3,5-dimethoxybenzyl)tryptophan
 111. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-[2-(trifluoromethyl)benzyl]tryptophan
 112. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-[3-(trifluoromethyl)benzyl]tryptophan
 113. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-[4-(trifluoromethyl)benzyl]tryptophan
 114. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-[4-(trifluoromethoxy)benzyl]tryptophan
 115. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(2-fluorobenzyl)tryptophan
 116. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(3-fluorobenzyl)tryptophan
 117. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-fluorobenzyl)tryptophan
 118. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(3,5-difluorobenzyl)tryptophan
 119. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-chlorobenzyl)tryptophan
 120. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-isopropylbenzyl)tryptophan
 121. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(2-cyanobenzyl)tryptophan
 122. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(3-cyanobenzyl)tryptophan
 123. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-cyanobenzyl)tryptophan
 124. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxytryptophan
 125. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(pyridin-3-ylmethyl)tryptophan
 126. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(4-carboxybenzyl)tryptophan
 127. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-methyltryptophan
 128. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-ethyltryptophan
 129. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-isobutyltryptophan
 130. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-pentyltryptophan
 131. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(cyclobutylmethyl)tryptophan
 132. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-carboxy-1-(cyclohexylmethyl)tryptophan
 133. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chlorotryptophan
 134. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyltryptophan
 135. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyanotryptophan
 136. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-(4-methylbenzyl)tryptophan
 137. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-(2-methoxybenzyl)tryptophan
 138. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-(3-methoxybenzyl)tryptophan
 139. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-(4-methoxybenzyl)tryptophan
 140. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-[4-(trifluoromethoxy)benzyl]tryptophan
 141. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-(4-fluorobenzyl)tryptophan
 142. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-(4-isopropylbenzyl)tryptophan
 143. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-cyano-1-isobutyltryptophan
 144. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyltryptophan
 145. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyl-1-(2-methylbenzyl)tryptophan
 146. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-methoxybenzyl)-2-methyltryptophan
 147. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-methoxybenzyl)-2methyltryptophan
 148. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methoxybenzyl)-2-methyltryptophan
 149. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyl-1-[3-(trifluoromethyl)benzyl]tryptophan
 150. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyl-1-[4-(trifluoromethyl)benzyl]tryptophan
 151. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyl-1-[4-(trifluoromethoxy)benzyl]tryptophan
 152. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-fluorobenzyl)-2-methyltryptophan
 153. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-fluorobenzyl)-2-methyltryptophan
 154. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-fluorobenzyl)-2-methyltryptophan
 155. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-difluorobenzyl)-2-methyltryptophan
 156. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-2-methyltryptophan
 157. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-isopropylbenzyl)-2-methyltryptophan
 158. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-cyanobenzyl)-2-methyltryptophan
 159. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-cyanobenzyl)-2-methyltryptophan
 160. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-cyanobenzyl)-2-methyltryptophan
 161. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyltryptophan
 162. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-2-methyl-1-(pyridin-3-ylmethyl)tryptophan
 163. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-ethyl-2-methyltryptophan
 164. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-isobutyl-2-methyltryptophan
 165. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclobutylmethyl)-2-methyltryptophan
 166. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclohexylmethyl)-2-methyltryptophan
 167. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyltryptophan
 168. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-(2-methylbenzyl)tryptophan
 169. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-(3-methylbenzyl)tryptophan
 170. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-methoxybenzyl)-5-methyltryptophan
 171. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-methoxybenzyl)-5-methyltryptophan
 172. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-[2-(trifluoromethyl)benzyl]tryptophan
 173. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-[3(trifluoromethyl)benzyl]tryptophan
 174. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-[4-(trifluoromethyl)benzyl]tryptophan
 175. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-fluorobenzyl)-5-methyltryptophan
 176. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-fluorobenzyl)-5-methyltryptophan
 177. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-difluorobenzyl)-5-methyltryptophan
 178. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-5-methyltryptophan
 179. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-isopropylbenzyl)-5-methyltryptophan
 180. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyltryptophan
 181. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-(pyridin-3-ylmethyl)tryptophan
 182. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-ethyl-5-methyltryptophan
 183. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-isobutyl-5-methyltryptophan
 184. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl-1-pentyltryptophan
 185. 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyltryptophan
 186. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-(2-methylbenzyl)tryptophan
 187. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-(3-methylbenzyl)tryptophan
 188. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-(4-methylbenzyl)tryptophan
 189. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(2-methoxybenzyl)-2-methyltryptophan
 190. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(3-methoxybenzyl)-2-methyltryptophan
 191. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1-(4-methoxybenzyl)-2-methyltryptophan
 192. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-dimethoxybenzyl)-5-methoxy-2-methyltryptophan
 193. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-[2-(trifluoromethyl)benzyl]tryptophan
 194. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-[3-(trifluoromethoxy)benzyl]tryptophan
 195. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-[4-(trifluoromethyl)benzyl]tryptophan
 196. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-[4-(trifluoromethoxy)benzyl]tryptophan
 197. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-fluorobenzyl)-5-methoxy-2-methyltryptophan
 198. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-fluorobenzyl)-5-methoxy-2-methyltryptophan
 199. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-fluorobenzyl)-5-methoxy-2-methyltryptophan
 200. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3,5-difluorobenzyl)-5-methoxy-2-methyltryptophan
 201. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-5-methoxy-2-methyltryptophan
 202. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-isopropylbenzyl)-5-methoxy-2-methyltryptophan
 203. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(2-cyanobenzyl)-5-methoxy-2-methyltryptophan
 204. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(3-cyanobenzyl)-5-methoxy-2-methyltryptophan
 205. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-cyanobenzyl)-5-methoxy-2-methyltryptophan
 206. 1-(1,3-benzodioxol-5-ylmethyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyltryptophan
 207. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-carboxybenzyl)-5-methoxy-2-methyltryptophan
 208. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-1,2-dimethyltryptophan
 209. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-ethyl-5-methoxy-2-methyltryptophan
 210. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-isobutyl-5-methoxy-2-methyltryptophan
 211. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyl-1-pentyltryptophan
 212. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclobutylmethyl)-5-methoxy-2-methyltryptophan
 213. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(cyclohexylmethyl)-5-methoxy-2-methyltryptophan
 214. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-hydroxybenzyl)-D-tryptophan
 215. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-ethoxybenzyl)-D-tryptophan
 216. 1-[4-(allyloxy)benzyl]-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-D-tryptophan
 217. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-meth-D(or L)-tryptophan
 218. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl(or D)-L-tryptophan
 219. 1-(tert-butoxycarbonyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-L-tryptophan
 220. 1-(tert-butoxycarbonyl)-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-D-tryptophan
 221. N-{[4-(but-2-ynyloxy)phenyl]sfonyl}-5-methoxy-D(or L)-tryptophan
 222. N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-methoxy-L(or D)-tryptophan
 223. 5-(benzyloxy)-N-{[4-(but-2-ynyloxy)phenyl]sulfon}-D(or L)-tryptophan
 224. 5-(benzyloxy)-N-{[4-(but-2-ynyloxy)phenyl]sulfon}-L(or D)-tryptophan; or a pharmaceutically acceptable salt thereof, prodrug thereof or a stereoisomer thereof.
 27. The compound of claim 1 that is selected from: N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-1-(4-methoxybenzyl)-D-tryptophan; N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methyl(or D)-L-tryptophan; N-{[4-(but-2-ynyloxy)phenyl]sfonyl}-5-methoxy-D(or L)-tryptophan; N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-chloro-1-(4-methoxybenzyl)-2-methyltryptophan; or 1-benzyl-N-{[4-(but-2-ynyloxy)phenyl]sulfonyl}-5-methoxy-2-methyltryptophan; or a pharmaceutically acceptable salt thereof or prodrug thereof.
 28. A method of treating or inhibiting a disease or disorder mediated by TNF-α in a mammal, which comprises providing to a mammal in need thereof an effective amount of a compound of claim
 1. 29. The method of claim 28 wherein the disease or disorder is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, osteoarthritis, tumor metastasis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, diabetes (insulin resistance), Crohn's disease, degenerative cartilage loss, asthma, idiopathic pulmonary fibrosis, vasculitis, systemic lupus erythematosus, irritable bowel syndrome, acute coronary syndrome, hepatitis C, cachexia, COPD or type 2 diabetes.
 30. A method of alleviating a symptom of a disease or disorder mediated by TNF-α in a mammal, which comprises providing to a mammal in need thereof an effective amount of a compound of claim
 1. 31. The method of claim 30 wherein the symptom of the disease or disorder is a symptom of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, osteoarthritis, tumor metastasis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, diabetes (insulin resistance), Crohn's disease, degenerative cartilage loss, asthma, idiopathic pulmonary fibrosis, vasculitis, systemic lupus erythematosus, irritable bowel syndrome, acute coronary syndrome, hepatitis C, cachexia, COPD or type 2 diabetes. 